Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Riccardo Nevola
 -- 4658 2023-07-20 10:51:51 |
2 format
Jason Zhu
 Meta information modification 4658 2023-07-21 07:26:04 | |
3 format
Jason Zhu
 Meta information modification 4658 2023-07-21 07:26:57 |

Video Upload Options

We provide professional Video Production Services to translate complex research into visually appealing presentations. Would you like to try it?
No, upload directly Yes

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Nevola, R.; Tortorella, G.; Rosato, V.; Rinaldi, L.; Imbriani, S.; Perillo, P.; Mastrocinque, D.; La Montagna, M.; Russo, A.; Di Lorenzo, G.; et al. Impact of Sex Hormones on Hepatocellular Carcinoma. Encyclopedia. Available online: https://encyclopedia.pub/entry/47027 (accessed on 17 November 2024).
Nevola R, Tortorella G, Rosato V, Rinaldi L, Imbriani S, Perillo P, et al. Impact of Sex Hormones on Hepatocellular Carcinoma. Encyclopedia. Available at: https://encyclopedia.pub/entry/47027. Accessed November 17, 2024.
Nevola, Riccardo, Giovanni Tortorella, Valerio Rosato, Luca Rinaldi, Simona Imbriani, Pasquale Perillo, Davide Mastrocinque, Marco La Montagna, Antonio Russo, Giovanni Di Lorenzo, et al. "Impact of Sex Hormones on Hepatocellular Carcinoma" Encyclopedia, https://encyclopedia.pub/entry/47027 (accessed November 17, 2024).
Nevola, R., Tortorella, G., Rosato, V., Rinaldi, L., Imbriani, S., Perillo, P., Mastrocinque, D., La Montagna, M., Russo, A., Di Lorenzo, G., Alfano, M., Rocco, M., Ricozzi, C., Gjeloshi, K., Sasso, F.C., Marfella, R., Marrone, A., Kondili, L.A., Esposito, N., ...Cozzolino, D. (2023, July 20). Impact of Sex Hormones on Hepatocellular Carcinoma. In Encyclopedia. https://encyclopedia.pub/entry/47027
Nevola, Riccardo, et al. "Impact of Sex Hormones on Hepatocellular Carcinoma." Encyclopedia. Web. 20 July, 2023.
Impact of Sex Hormones on Hepatocellular Carcinoma
Edit
This entry is adapted from the peer-reviewed paper 10.3390/biology12070984

Several chronic liver diseases are characterized by a clear gender disparity. Among them, hepatocellular carcinoma (HCC) shows significantly higher incidence rates in men than in women. The different epidemiological distribution of risk factors for liver disease and HCC only partially accounts for these gender differences. In fact, the liver is an organ with recognized sexual dysmorphism and is extremely sensitive to the action of androgens and estrogens. Sex hormones act by modulating the risk of developing HCC and influencing its aggressiveness, response to treatments, and prognosis. Furthermore, androgens and estrogens are able to modulate the action of other factors and cofactors of liver damage (e.g., chronic HBV infection, obesity), significantly influencing their carcinogenic power.

hepatocellular carcinoma HCC sex hormones androgens

1. Estrogens

Estrogens are steroid hormones mainly produced in the ovary, placenta, corpora lutea, adrenal glands, and adipose tissue and are responsible for the development of the female reproductive system and secondary sexual characteristics [1][2]. Four types are recognized: estrone (E1), 17β-estradiol (E2), estriol (E3), and estetrol (E4). These hormones exert their action through binding with estrogen receptors (ER) α and β, located in the nucleus and cell membrane, and with the membrane receptor G-protein coupled estrogen receptor (GPER) [3][4]. Therefore, estrogens are able to activate the intracellular signaling cascade both through binding with ERα, Erβ, and GPER receptors, and through entry into the plasma membrane, interacting directly with intracellular ERα and ERβ. The receptor activation induces transcriptional processes and/or signaling events able to modulate the gene expression through mechanisms that predict (genomic) or do not predict (nongenomic) the direct link between the receptor complex and specific DNA sequences [3]. Genomic effects are induced by migration of the estrogen receptor complexes towards the nucleus and direct interaction with specific DNA sequences known as estrogen response elements (EREs) [5]. In addition, approximately one-third of genes whose transcription is estrogen-dependent have been shown to lack specific ERE regions [6]. In fact, these hormones have the ability to transduce the signal even in the absence of a direct link with the target DNA. In fact, they can interact with specific transcription factors, such as activator protein-1 (AP-1) and stimulating protein-1 (Sp-1), able to act on a multitude of target genes and significantly amplify the ability of estrogen-mediated gene regulation [3]. Nongenomic effects are based on indirect regulation of gene expression through complex intracellular signaling events, mainly involving phospholipase C (PLC)/protein kinase C (PKCs), phosphatidyl inositol 3 kinase (PI3K)/Akt kinase, Ras /Raf/MAPK, and cAMP/protein kinase A (PKA). Finally, numerous interactions between genomic and nongenomic signal transduction pathways have been demonstrated [3][7].
Estrogens play a role in numerous functions, including the development of primary and secondary female sexual characteristics, the regulation of reproductive mechanisms and the menstrual cycle, bone metabolism, cholesterol mobilization, and inflammation control, also influencing the function of other systems (e.g., cardiovascular and nervous) [3][8][9]. In males, a low level of estrogen is essential for sperm maturation and erectile function. Due to the role played in the modulation of numerous functions, their dysregulation is crucial in the pathogenesis of a variety of diseases, including cardiovascular (e.g., atherosclerosis, arterial hypertension), metabolic (e.g., metabolic syndrome, dyslipidemia), bone (e.g., postmenopausal osteoporosis), and central nervous system (e.g., Alzheimer’s disease, psychiatric disorders) diseases [10][11][12][13][14][15]. In oncology, estrogens play a key role in the development of breast cancer (where the binding of female hormones with ERα stimulates cell proliferation, while the binding with ERβ plays an antiproliferative role), ovarian cancer, and endometrial cancer, but also in the incidence of mesothelioma, meningioma, prostate cancer, renal cell carcinoma, colorectal, and lung cancer [16].

1.1. PTPRO

The receptor-type tyrosine-protein phosphatase O (PTPRO) is a member of the protein tyrosine phosphatases (PTPs) family that acts as a mediator of cell signaling pathways by inhibiting tumor proliferation and degeneration [17]. The PTPRO gene shows three ERE regions at the promoter level, strictly dependent on estrogens action and their binding to ERα [18]. Recent studies highlight its role as a tumor suppressor in different types of neoplasms, such as lung [19], renal [20], and colorectal cancer [21]. Indeed, PTPRO appears able to inhibit Janus kinase 2 (JAK2) and phosphoinositide 3-kinase (PI3K) dephosphorylation which are crucial in the activation of the transcription factor STAT3. Therefore, the suppressive role of PTPRO in cancer is due to STAT3 inactivation, which instead appears upregulated when PTPRO levels are reduced [22]. In the HCC setting, STAT3 plays a central role in the processes of development, progression, and metastasis [23]. Hou et al. [18] demonstrated that PTPRO levels are strongly reduced in HCC cell lines when compared with those in adjacent healthy tissues, resulting in STAT3 overexpression, and that tumor number and size were increased in PTPRO knockout mice. Furthermore, PTPRO levels in male adjacent tissue were lower than in female tissue [18]. Through ERα activation and binding to ERE regions, estrogens could induce PTPRO overexpression, favoring STAT3 inhibition. They would therefore act by reducing the risk of developing HCC and, when it develops, favoring less aggressiveness and consequently a better prognosis. The role of PTPRO would therefore contribute to the gender differences observed in the HCC setting.

1.2. Foxa1 and Foxa2

Forkhead box (Fox) transcription factors are a family of transcription factors derived from the Fox genes and involved in hormonal and immune system regulation, embryogenesis, cell proliferation, and growth through the regulation of the epithelial-mesenchymal transition [24]. In oncology, they have a role in tumor development and in progression and metastasis processes, including breast, ovarian, and prostate cancer, and HCC [25]. Fox transcription factors are categorized into subclasses A to S [26]. Recently it has been highlighted that FoxC1 is able to promote the development of HCC and metastasis [27]. However, to date it has no known impact on gender differences in this setting. Conversely, Foxa1 and Foxa2, as well as being crucial in liver development and differentiation, are responsible for the sexual dysmorphism of HCC [28][29]. Li et al. [29] evaluated the role of these transcription factors in Foxa1- and Foxa2-deficient mice after DEN-induced hepatocarcinogenesis. The authors showed that in the absence of Foxa1/a2, the sexually dimorphic HCC is completely inverted and that Foxa1/a2-deficient females show greater size and more frequent multifocality than non-Foxa1/2-deficient controls. In deficient mice, coregulation of target genes by Foxa1/a2 and either the ERα or the androgen receptor was lost. Foxa and ERα modulate several pathways in resistance to HCC. In particular, the Myc oncogene seems crucial in the oncoprotection mechanisms exerted by Foxa and ERα. Myc is, in fact, significantly inhibited by Foxa and Erα, and is overexpressed in conditions with Foxa1/a2 deficiency. When Myc expression is suppressed, hepatocyte proliferation and the likelihood of neoplastic transformation are greatly reduced. In order to perform this, it has been hypothesized that a coregulation of both Foxa1/a2 and ERα is necessary. By itself, ERα does not appear to be able to inhibit Myc. Indeed, in absence of Foxa1/a2, estrogens would seem to favor hepatocarcinogenesis. Foxa1/2 gene polymorphisms are associated with decreased binding of Foxa2 and ERα to their targets in the liver and correlate with HCC development in women. In males, on the other hand, an opposite mechanism seems to take place. In Foxa1/a2-deficient male mice, there is a reduced incidence of HCC and lower tumor burden. It has been hypothesized that Foxa1/a2 and AR cooperate in the regulation of gene expression and that Foxa1/a2 are essential for androgen signaling in promoting HCC development in male mice. Overall, these data confirm that the estrogen-dependent resistance to the development of HCC in females and the androgen-dependent favorability in males are mediated by Foxa1/2. As already described for PTPRO, the role of Fox transcription factors also appears to be decisive for the sexual dimorphism of HCC.

1.3. GPER

As already mentioned, GPER is a more recently discovered membrane estrogen receptor [4]. In addition to its already known functions, some studies have hypothesized a protective role of GPER against the development of HCC. GPER knockout mouse models indeed show a significant increase in inflammation (expressed by increased levels of IL-6) and liver fibrosis and accelerated hepatocarcinogenesis [30]. Furthermore, GPER levels are significantly lower in HCC compared with nontumor tissues. In HCC patients, GPER-positive patients more frequently show small tumor size, low serum alpha fetoprotein levels, and longer OS than GPER-negative patients [31]. The protective action of GPER against the development of HCC would depend on the ability to suppress the inflammatory response in the tumor microenvironment [30]. Furthermore, GPER is also able to modulate the estradiol-dependent expression of Sin1, the regulatory subunit of mTOR complex 2 (mTORC2) activity [32]. Via phosphorylation mechanisms, mTORC2 controls AKT activation through which GPER influences cell proliferation and hepatocarcinogenesis. Treatment with GPER-specific agonists has been shown to activate EGFR/ERK signaling pathways, thereby promoting apoptosis and inhibiting cell growth [31].

1.4. Inflammation

The development of HCC is closely related to tissue inflammation [33]. In fact, the liver has a marked innate immunity characterized above all by a significant proportion of natural killer cells (NK) and macrophages (KCs, Kupffer cells) [34]. If the innate immune system provides a rapid initial response to a broad range of hepatic insults, the adaptive immune system provides a specific immune response against pathogenic noxae to which the liver has been previously exposed. However, chronic inflammatory stimuli (e.g., chronic HBV or HCV infection, alcohol, NAFLD) can activate hepatic stellate cells (HSC), which, by differentiating into myofibroblasts, determine collagen deposition and consequent tissue fibrosis [35]. Chronic liver damage and inflammation are the cause of cell regeneration and production of reactive oxygen species (ROS), with potential damage to hepatocyte DNA and development of procarcinogenic mutations, which ultimately can lead to HCC. If chronic inflammatory processes are crucial in hepatocarcinogenesis, the influence of sex hormones on the mechanisms of onset and persistence of inflammation could play a decisive role in developing HCC. The main pathways by which sex hormones influence the inflammatory response and the risk of HCC known to date are described below.

IL-6

Interleukin 6 (IL-6) is a multifunctional inflammatory cytokine involved in the development of inflammation and cell proliferation [36]. In the liver, it is produced by Kuppfer cells and is a significant inducer of acute phase and infection defense responses [37]. Furthermore, IL-6 acts as a hepatocyte mitogen, with a role in the mechanisms of liver regeneration and the development of neoplasms. IL-6 binding to the IL-6 receptor (IL-6R) activates the Janus kinase (JAK), stimulating phosphorylation and activating signal transducers and activators of transcription 3 (STAT3) [38]. Activation of the IL-6/STAT3 axis is responsible for the role of IL-6 in the processes of anti-apoptosis, proliferation, invasion, angiogenesis, and metastasis. In patients with HCC, IL-6 levels are significantly increased and correlate with the occurrence of HCC and prognosis [39]. In females, high serum IL-6 levels have been shown to be an independent risk factor for HCC development (hazard ratio, HR: 1.61) [40]. Naugler et al. [41] investigated the role of IL-6 in HCC gender differences. The authors noted that after administration of the carcinogen DEN serum, IL-6 levels increased more in males than in females. Furthermore, the inhibition of IL-6 is able to cancel the gender differences in hepatocarcinogenesis. After DEN administration, IL6 −/− knockout mice show less apoptosis, liver cell proliferation, and necrosis than wild type mice. Collectively, these data indicate that the development of HCC is associated with elevated IL-6 levels and that IL-6 contributes to gender differences. This hypothesis is confirmed by the evidence that some IL-6 polymorphisms have been associated with the onset of HCC [42]. The protective effect of the female gender would occur mainly among carriers of phenotypes characterized by high IL-6 production. Furthermore, since oophorectomy is able to cancel gender disparities, it is conceivable that estrogens play a crucial role in this setting [41]. Indeed, female sex hormones would be able to inhibit the production of IL-6 from KCs through the suppression of the transcription factors NF-kappaB and C/EBP-β [43], with a protective effect on the development of HCC in females.

Tumor-Associated Macrophages

Within the tumor microenvironment, tumor-associated macrophages (TAMs) have an active role in the genesis and progression of the tumor [44]. Macrophage activation consists of two pathways, the classic one (M1) and an alternative one (M2) [45]. Macrophages acquiring an M2 phenotype are able to infiltrate tumor tissues guided by tumor- and T-cell-produced cytokines and promote tumor growth. Yang et al. [46] showed that estrogens act by inhibiting the alternative activation pathway of TAMs. In particular, 17β-estradiol is able to prevent the binding between ERβ and ATPase-coupling factor 6 (ATP5J) through the suppression of IL4-mediated phosphorylation of the transcription factors JAK1 and STAT6, thus inhibiting the JAK1-STAT6 signaling pathway. In this way, 17β-estradiol could suppress tumor growth by regulating the macrophage’s polarization.

NLRP3

The NLRP3 inflammasome is an intracellular multiprotein complex mediating innate immunity that assembles in response to cellular insults [47]. When assembled, NLP3 activates caspase-1, which is responsible for the release of inflammatory cytokines (interleukin-1β–IL-1β, and inteleukin-18–IL-18) and the promotion of pyroptosis, that is, of inflammatory cell death resulting from the formation of pores on the cell membrane [48]. Wei et al. [49] analyzed the role of the NLRP3 inflammasome in the development and progression of HCC, and they found that the expression of the NLRP3 inflammasome was completely lost or significantly downregulated in HCC tissue. Due to the loss of the protective and antiproliferative functions of the inflammasome, this deregulation of the NLRP3 in HCC correlates with poor histological differentiation and with increased tumor progression. The same authors also demonstrated that treatment with 17β-estradiol can lead to significant upregulation of the NLRP3 inflammasome via the E2/ERβ/MAPK pathway [50]. Therefore, estrogens would be able to suppress the development and progression of HCC also through stimulation of the NLRP3 inflammasome.

2. Androgens

Androgens are steroidal sex hormones essential for both sexes, however the serum concentration is significantly higher in men than in women [51]. These hormones are produced by adult female ovaries, male heads, and in adrenal glands, playing a central role in the development of sexual characteristics and mechanisms of reproduction. Furthermore, androgens are also necessary precursors for estrogen biosynthesis. In adult men, testosterone is the predominantly represented androgen hormone, which can be converted to dihydrotestosterone (DHT), the most potent endogenous androgen with 5 to 10 times higher affinity for the androgen receptor (AR) than that of testosterone [52]. The binding of androgens to their AR causes a change in receptor conformation with translocation of the complex into the nucleus and interaction with specific DNA sequences, the androgen response elements (AREs) [53]. Ultimately these regulate the transcription of a series of genes, including those responsible for cell growth and survival, which therefore appear sensitive to androgenic action.
Although they have a less defined role than estrogens, androgens also play important functions in the pathogenesis of HCC. Indeed, AR expression is increased in HCC tissue compared with normal liver, and mice lacking hepatic ARs develop HCC later and less frequently than wild-type mice [54]. Furthermore, AR overexpression is associated with disease progression and is an independent predictor of OS [55]. In particular, AR overexpression alters 67% of the AR target genes in HCC cells and promotes cell growth and oncogenic proliferation. Differently from prostate cancer, mechanistic target of rapamycin (mTOR) protein, a key member of the PI3K-AKT-mTOR signaling pathway frequently hyperactivated in several malignancies, stimulates AR transcriptional activity in HCC. The frequent activation of mTOR signaling pathways could represent a plausible molecular mechanism for nuclear AR overexpression in HCC. Furthermore, according to Feng et al. [56], AR activation would lead to greater transcription of the cell cycle-related kinase (CCRK) regulator, a critical mediator of AR signaling that appears markedly increased in HCC. CCRK would drive the processes of hepatocarcinogenesis by stimulating the signaling cascade mediated by β-catenin and T-cell factor. Overexpression of CCRK seems to be able to determine AR-induced cell cycle stimulation, hepatocellular proliferation, and malignant transformation.
In addition to the role directly played by male sex hormones and RA in the pathogenesis of HCC and its male predominance, androgens are also able to significantly enhance the oncogenic power of HBV infection [57]. The role of the androgen/AR axis in the pathogenesis of HCC during chronic HBV infection will be discussed in the next section.
In light of the male predominance in HCC incidence and the role of androgens and AR in oncogenic proliferation, anti-androgen and anti-AR therapies have been tested in the treatment of liver cancer. However, the results obtained were unsatisfactory [58]. Despite the relevant role played by the androgen/AR axis in the pathogenesis of HCC, probably only a small proportion of liver cancers (about one third) overexpress AR and could be responsive to AR inhibition [55]. In order to maximize treatments for HCC, the tumor biology in each patient (assessed by liver biopsy or, hopefully, by liquid biopsy) should guide the personalization of treatment, tending increasingly towards precision medicine [59].

3. Influence of Sex Hormones on Other Risk Factors for HCC

In addition to acting directly on the risk of developing HCC, sex hormones are also able to modulate the action of other factors and cofactors of liver damage, significantly influencing their carcinogenic potential.

3.1. Chronic Viral Hepatitis

Beyond the epidemiological differences in gender distribution, some evidence suggests that both chronic HCV and HBV infections are associated with a greater probability of developing HCC in males rather than in females. The gender difference in the risk of developing HCC during HBV infection appears to be extremely relevant. Indeed, the male-to-female ratio for HBV-related HCC is significantly higher than that for HCV-related HCC [60]. Overall, the incidence of HCC is 5- to 7-fold higher in male HBV carriers than in female ones, making male gender an important risk factor for HBV-related hepatocarcinogenesis. Since higher serum viral loads are associated with increased risk of HCC, the gender effect could be mediated by higher replicative levels observed in men compared to women [57]. Gender differences in HBV viral load levels could be influenced directly by the regulation of viral gene expression and indirectly by host immune responses modulation. Indeed, estrogens and androgens determine an opposite regulation of HBV transcription [57]. Stimulation of the AR by androgens is able to increase overall HBV transcription [61], and vice versa, hepatitis B virus X protein (HBx), involved in viral replication mechanisms, has been shown to increase hepatic AR activity in an androgen-dependent manner [62]. Indeed, a positive cycle is created that is able to aberrantly activate and maintain the activity of hepatic RA, elevate viral replication levels, and enhance the oncogenic risk in male patients with HBV infection [57]. On the other hand, in light of the evidence that the incidence of HBV-related HCC is more frequent in postmenopausal than in premenopausal women, it has been hypothesized that estrogens may also play a central role in regulating oncogenic risk during chronic HBV infection [63]. In contrast to the viral replication-promoting role of the androgen/AR axis, the action of estrogens results in a reduction in viraemia levels in the host. In particular, estrogens support the hepatic expression of its nuclear receptor ERα, which can suppress the modulating activity of viral enhancer I and consequently reduce HBV transcription [64]. Overall, HBV is therefore considered a sex hormone responsive virus, whose replication is stimulated by androgens and inhibited by estrogens. The different levels of viraemia (higher in humans) resulting from this hormonal effect could explain at least in part the gender differences in the risk of developing HCC during HBV infection. However, in addition to the direct action of sex hormones on the virus life cycle, the modulation of oncogenic risk exerted by sex hormones in HBV-related HCC could also be mediated by the ability to influence the immune response to HBV infection [57]. Thanks to a more intense immune response, clearance of the hepatitis B envelope (HBeAg) and surface (HBsAg) antigen and the relative seroconversion are more frequent in women and the protective response conferred by vaccination is more significant. Although the mechanisms of this disparity are still unclear, it is known that the androgen/AR axis is capable of exerting immunosuppressive effects on the development and activation of T cells [65], amplifying the action already exerted by the virus itself [66]. The higher levels of viral replication secondary to such immunosuppressive effects could be a crucial cofactor for higher risk of HCC in HBV-infected men compared to women.
Similar to what occurs during HBV infection, in chronic hepatitis C, male gender has been shown to be an independent risk factor for faster progression rate towards cirrhosis and consequently for HCC [67]. Similar to HBx for HBV infection, HCV core protein has been shown to increase AR-mediated transcriptional activity via activation of the JAK/STAT pathway [68]. Since the vascular endothelial growth factor (VEGF) is a target gene of AR in the liver and plays an important role in tumor angiogenesis, the increased transcriptional activity of AR leads to higher risk of developing HCC in HCV-infected patients. As concerns female sex hormones, estrogen affects HCV replication through viral interactions with estrogen receptors. In particular, estradiol has been shown to stimulate the production of interferon-γ (IFN-γ), which can inhibit tumor growth [69]. In HCC, IFN-γ indeed induces autophagy processes, determining growth inhibition and cell death through interferon-regulatory factor-1 (IRF-1). Furthermore, the activation of the membrane estrogen receptor GPER is able to increase metallopeptidase MMP-9 levels [70]. The latter has the ability to cleave and block the activity of occludins, structural proteins of membrane tight junctions, used by HCV to enter cells. Therefore, high estrogenic activity, as occurs in premenopausal women, limits the cytolytic and replicative activity of HCV, reduces the rate of liver damage progression, and, at the same time, the risk of HCC.

3.2. Obesity

Obesity is an independent risk factor for malignancies, including HCC. As already discussed, to date it is the cause of about 9% of HCC cases worldwide [71], increasing the oncogenic risk by 2 to 4 times in presence of damaging cofactors [72][73]. In addition to the pro-oncogenic risk resulting from the development of nonalcoholic steatohepatitis (NASH) and metabolic cirrhosis, obesity may favor HCC occurrence even in absence of significant liver fibrosis by promoting systemic and hepatic inflammation, inducing oxidative stress and lipotoxicity, stimulating the insulin-like growth factor-1 (IGF-1) axis by hyperinsulinemia, and favoring hormonal changes [74]. In this regard, obesity is associated with high levels of leptin, a hormone produced by adipose tissue and the small intestine, which is crucial in regulating mechanisms of energy balance and body weight control [75]. Although, at the central level, it influences the hypothalamic-pituitary-adrenal axis by regulating feelings of hunger, in the periphery, it is able to influence the reproductive system, the basal metabolic rate, the production and sensitivity to insulin, and regulate both the innate and acquired immunity. As a compensatory mechanism to preserve insulin sensitivity, leptin levels increase with increasing fatty mass, but persistent hyperleptinemia is associated with more severe liver steatosis and is involved in fibrinogenesis and hepatocarcinogenesis processes [76][77]. In addition to its role as regulator of energy balance, leptin can in fact act as a growth factor and promote the development of neoplasms. In the liver, it has been shown to promote the development of HCC, as well as its progression, invasiveness, and migration through the activation of the JAK/STAT pathway [78]. In light of the higher incidence of HCC in men than in women, a potential inhibitory effect of estrogens on leptin-induced HCC has been hypothesized. Shen et al. [79] demonstrated that 17β-estradiol is able to suppress leptin-induced liver tumor cell proliferation and promote cell apoptosis. This effect is achieved through estrogen binding to both ER-β, with consequent reversal of leptin-induced changes in SOCS3/STAT3 and p38/MAPK activation, and ER-α, as well as to GPER, with secondary activation of the ERK pathway. The overall effect of estrogen would therefore be to antagonize the oncogenic actions of leptin.
Similar to leptin, adiponectin is another hormone produced by adipose tissue and its role is crucial in the mechanisms of metabolism regulation, sensitivity to insulin action, and inflammation [80]. In the liver, adiponectin has demonstrated an antisteatotic action, stimulating the beta-oxidation of fatty acids and reducing tumor necrosis factor (TNF)-α circulating levels [81]. Furthermore, it is protective against HCC development through the activation of AMP-activated protein kinase (AMPK) [82]. Serum adiponectin levels tend to decrease in the case of insulin resistance, such as in obesity and/or diabetes mellitus [80], and in males [83]. Compared to women, serum adiponectin levels are significantly reduced in men. In conditions of obesity and insulin resistance, the reduction in adiponectin seems responsible for the increased HCC risk in males [82]. Since higher adiponectin levels have been found after castration in males, it seems likely that androgens are the most responsible for gender disparities in adipokine concentrations. In particular, testosterone could activate the c-Jun N-terminal kinases (JNK) protein, resulting in inhibition of adiponectin secretion and increased risk of HCC.

4. Interaction between Sex Hormones and miRNAs

Gender differences in the expression of microRNAs have recently emerged (miRNAs) in the context of HCC and in the influence exerted on them by sexual hormones. MiRNAs are small, noncoding, single-stranded RNAs that play the role of posttranscriptional regulators of protein encoding genes [84]. They interact with the 3′ region of the target mRNA influencing its transcription processes. Changes in miRNA expression are crucial in the regulation of complex genetic networks and cellular signaling cascades. At the same time, altered miRNA expression plays a central role in the regulation of protein expression within the pathological changes of numerous diseases. For example, several miRNAs (e.g., miR-122, miR-21, miR-34a, miR-451) are enhanced in patients with NAFLD [85]. Aberrant miRNA expression can be frequently encountered in several human cancers. Genomic regions encoding miRNAs can protect against genetic mutations, whereas carcinogenesis-related transcription factors can suppress some miRNAs and favor the development of pro-oncogenic mutations [86]. In recent years, numerous data have emerged on the role of miRNAs in the genesis and progression of liver cirrhosis and in HCC occurrence [87]. In the liver cancer setting, several HCC-associated miRNAs (miR-21, miR-221, miR-222) are increased, whereas others (miR-122a, miR-145, miR-199a, miR-223) are decreased. Indeed, healthy hepatocytes and HCC cells express different miRNA profiles [88].
Recently, significant gender differences in miRNA expression have emerged in patients with HCC, with close correlation with sex hormones. Among others, miR-216a appears significantly upregulated in HCC cells, particularly in male patients [89]. Through AR, androgens are able to bind AREs in the promoter region of pri-miR-216a and determine a significant increase in its transcription. Moreover, during chronic HBV infection, the HBx viral protein is able to further enhance the AR-mediated protranscriptional effect. Unlike the male prevalence of mir-216a, miR-18a appears significantly increased in women with HCC (female/male ratio: 4.58) [90]. miR-18a is able to bind to the 3′UTR region of the ESR1 gene mRNA which codes for the ERα estrogen receptor, inhibiting its transcription. In HCC cells, overexpression of miR-18a decreased ERα levels. Therefore, it inhibits the protective effects of estrogen, promoting hepatocarcinogenesis in women.
A similar action is also performed by miR-22 [91]. This miRNA is in fact able to inhibit the activity of ERα through binding to the 3′UTR region of its mRNA, compromising the estrogen signaling cascade. In male HBV-infected patients, miR-22 has been shown to promote the development of HCC [92]. Indeed, overexpression of miR-22 in male HBV-related HCC adjacent tissue correlates with downregulated ERα. This phenomenon could mitigate the protective effect of estrogens on HCC occurrence in male HBV-infected patients. The downregulation of ERα secondary to miR-22 overexpression could also lead to an increase in IL-1α expression. The latter is a cytokine released in response to hepatic necrosis able to determine a compensatory proliferative response [93]. Its increase could further contribute to loss of estrogen’s protective mechanisms against the development of HCC [92].
Zhao et al. [94] finally evaluated the expression of the miR-545/374a cluster in the HBV-related HCC setting. In fact, in the presence of the viral protein HBx, there is a significant increase in miR-545/374a expression in males (but not in females) with HBV-related HCC. Encoded by the Ftx gene, these miRNAs are overexpressed in HCC secondary to HBV infection and are associated with poorer prognosis. Furthermore, estrogen-related receptor gamma (ESRRG), a protein belonging to the ER-like receptor family, is inversely correlated with miR-545 expression. However, its role in the development of HCC has not been clarified yet.

References

  1. Cui, J.; Shen, Y.; Li, R. Estrogen synthesis and signaling pathways during aging: From periphery to brain. Trends Mol. Med. 2013, 19, 197–209.
  2. Holinka, C.F.; Diczfalusy, E.; Coelingh Bennink, H.J. Estetrol: A unique steroid in human pregnancy. J. Steroid. Biochem. Mol. Biol. 2008, 110, 138–143.
  3. Fuentes, N.; Silveyra, P. Estrogen receptor signaling mechanisms. Adv. Protein Chem. Struct. Biol. 2019, 116, 135–170.
  4. Xu, S.; Yu, S.; Dong, D.; Lee, L.T.O. G Protein-Coupled Estrogen Receptor: A Potential Therapeutic Target in Cancer. Front. Endocrinol. 2019, 10, 725.
  5. Klinge, C.M. Estrogen receptor interaction with estrogen response elements. Nucleic Acids Res. 2001, 29, 2905–2919.
  6. Vrtačnik, P.; Ostanek, B.; Mencej-Bedrač, S.; Marc, J. The many faces of estrogen signaling. Biochem. Med. 2014, 24, 329–342.
  7. Björnström, L.; Sjöberg, M. Mechanisms of estrogen receptor signaling: Convergence of genomic and nongenomic actions on target genes. Mol. Endocrinol. 2005, 19, 833–842.
  8. Iorga, A.; Cunningham, C.M.; Moazeni, S.; Ruffenach, G.; Umar, S.; Eghbali, M. The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy. Biol. Sex Differ. 2017, 8, 33.
  9. Bustamante-Barrientos, F.A.; Méndez-Ruette, M.; Ortloff, A.; Luz-Crawford, P.; Rivera, F.J.; Figueroa, C.D.; Molina, L.; Bátiz, L.F. The Impact of Estrogen and Estrogen-Like Molecules in Neurogenesis and Neurodegeneration: Beneficial or Harmful? Front. Cell. Neurosci. 2021, 15, 636176.
  10. Knowlton, A.A.; Lee, A.R. Estrogen and the cardiovascular system. Pharmacol. Ther. 2012, 135, 54–70.
  11. Wehbe, Z.; Nasser, S.A.; El-Yazbi, A.; Nasreddine, S.; Eid, A.H. Estrogen and Bisphenol A in Hypertension. Curr. Hypertens. Rep. 2020, 22, 23.
  12. Mahboobifard, F.; Pourgholami, M.H.; Jorjani, M.; Dargahi, L.; Amiri, M.; Sadeghi, S.; Tehrani, F.R. Estrogen as a key regulator of energy homeostasis and metabolic health. Biomed. Pharmacother. 2022, 156, 113808.
  13. Fischer, V.; Haffner-Luntzer, M. Interaction between bone and immune cells: Implications for postmenopausal osteoporosis. Semin. Cell. Dev. Biol. 2022, 123, 14–21.
  14. Bagit, A.; Hayward, G.C.; MacPherson, R.E.K. Exercise and estrogen: Common pathways in Alzheimer’s disease pathology. Am. J. Physiol. Endocrinol. Metab. 2021, 321, E164–E168.
  15. Hwang, W.J.; Lee, T.Y.; Kim, N.S.; Kwon, J.S. The Role of Estrogen Receptors and Their Signaling across Psychiatric Disorders. Int. J. Mol. Sci. 2020, 22, 373.
  16. Liang, J.; Shang, Y. Estrogen and cancer. Annu. Rev. Physiol. 2013, 75, 225–240.
  17. Tautz, L.; Critton, D.A.; Grotegut, S. Protein tyrosine phosphatases: Structure, function, and implication in human disease. Methods Mol. Biol. 2013, 1053, 179–221.
  18. Hou, J.; Xu, J.; Jiang, R.; Wang, Y.; Chen, C.; Deng, L.; Huang, X.; Wang, X.; Sun, B. Estrogen-sensitive PTPRO expression represses hepatocellular carcinoma progression by control of STAT3. Hepatology 2013, 57, 678–688.
  19. Ming, F.; Sun, Q. Epigenetically silenced PTPRO functions as a prognostic marker and tumor suppressor in human lung squamous cell carcinoma. Mol. Med. Rep. 2017, 16, 746–754.
  20. Gan, J.; Zhang, H. PTPRO predicts patient prognosis and correlates with immune infiltrates in human clear cell renal cell carcinoma. Transl. Cancer Res. 2020, 9, 4800–4810.
  21. Dai, W.; Xiang, W.; Han, L.; Yuan, Z.; Wang, R.; Ma, Y.; Yang, Y.; Cai, S.; Xu, Y.; Mo, S.; et al. PTPRO represses colorectal cancer tumorigenesis and progression by reprogramming fatty acid metabolism. Cancer Commun. 2022, 42, 848–867.
  22. Zhang, W.; Liu, Y.; Yan, Z.; Yang, H.; Sun, W.; Yao, Y.; Chen, Y.; Jiang, R. IL-6 promotes PD-L1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type O expression in human hepatocellular carcinoma. J. Immunother. Cancer 2020, 8, e000285.
  23. Lee, C.; Cheung, S.T. STAT3: An Emerging Therapeutic Target for Hepatocellular Carcinoma. Cancers 2019, 11, 1646.
  24. Castaneda, M.; Hollander, P.D.; Mani, S.A. Forkhead Box Transcription Factors: Double-Edged Swords in Cancer. Cancer Res. 2022, 82, 2057–2065.
  25. Gong, Z.; Yu, J.; Yang, S.; Lai, P.B.S.; Chen, G.G. FOX transcription factor family in hepatocellular carcinoma. Biochim. Biophys. Acta Rev. Cancer 2020, 1874, 188376.
  26. Golson, M.L.; Kaestner, K.H. Fox transcription factors: From development to disease. Development 2016, 143, 4558–4570.
  27. Lin, Z.; Huang, W.; He, Q.; Li, D.; Wang, Z.; Feng, Y.; Liu, D.; Zhang, T.; Wang, Y.; Xie, M.; et al. FOXC1 promotes HCC proliferation and metastasis by Upregulating DNMT3B to induce DNA Hypermethylation of CTH promoter. J. Exp. Clin. Cancer Res. 2021, 40, 50.
  28. Lee, C.S.; Friedman, J.R.; Fulmer, J.T.; Kaestner, K.H. The initiation of liver development is dependent on Foxa transcription factors. Nature 2005, 435, 944–947.
  29. Li, Z.; Tuteja, G.; Schug, J.; Kaestner, K.H. Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer. Cell 2012, 148, 72–83.
  30. Wei, T.; Chen, W.; Wen, L.; Zhang, J.; Zhang, Q.; Yang, J.; Liu, H.; Chen, B.W.; Zhou, Y.; Feng, X.; et al. G protein-coupled estrogen receptor deficiency accelerates liver tumorigenesis by enhancing inflammation and fibrosis. Cancer Lett. 2016, 382, 195–202.
  31. Qiu, Y.A.; Xiong, J.; Fu, Q.; Dong, Y.; Liu, M.; Peng, M.; Jin, W.; Zhou, L.; Xu, X.; Huang, X.; et al. GPER-Induced ERK Signaling Decreases Cell Viability of Hepatocellular Carcinoma. Front. Oncol. 2021, 11, 638171.
  32. Feng, G.; Cai, J.; Huang, Y.; Zhu, X.; Gong, B.; Yang, Z.; Yan, C.; Hu, Z.; Yang, L.; Wang, Z. G-Protein-Coupled Estrogen Receptor 1 Promotes Gender Disparities in Hepatocellular Carcinoma via Modulation of SIN1 and mTOR Complex 2 Activity. Mol. Cancer Res. 2020, 18, 1863–1875.
  33. Yang, Y.M.; Kim, S.Y.; Seki, E. Inflammation and Liver Cancer: Molecular Mechanisms and Therapeutic Targets. Semin. Liver Dis. 2019, 39, 26–42.
  34. Parlar, Y.E.; Ayar, S.N.; Cagdas, D.; Balaban, Y.H. Liver immunity, autoimmunity, and inborn errors of immunity. World J. Hepatol. 2023, 15, 52–67.
  35. Refolo, M.G.; Messa, C.; Guerra, V.; Carr, B.I.; D’Alessandro, R. Inflammatory Mechanisms of HCC Development. Cancers 2020, 12, 641.
  36. Hirano, T. IL-6 in inflammation, autoimmunity and cancer. Int. Immunol. 2021, 33, 127–148.
  37. Schmidt-Arras, D.; Rose-John, S. IL-6 pathway in the liver: From physiopathology to therapy. J. Hepatol. 2016, 64, 1403–1415.
  38. Xu, J.; Lin, H.; Wu, G.; Zhu, M.; Li, M. IL-6/STAT3 Is a Promising Therapeutic Target for Hepatocellular Carcinoma. Front. Oncol. 2021, 11, 760971.
  39. Soresi, M.; Giannitrapani, L.; D’Antona, F.; Florena, A.M.; La Spada, E.; Terranova, A.; Cervello, M.; D’Alessandro, N.; Montalto, G. Interleukin-6 and its soluble receptor in patients with liver cirrhosis and hepatocellular carcinoma. World J. Gastroenterol. 2006, 12, 2563–2568.
  40. Nakagawa, H.; Maeda, S.; Yoshida, H.; Tateishi, R.; Masuzaki, R.; Ohki, T.; Hayakawa, Y.; Kinoshita, H.; Yamakado, M.; Kato, N.; et al. Serum IL-6 levels and the risk for hepatocarcinogenesis in chronic hepatitis C patients: An analysis based on gender differences. Int. J. Cancer 2009, 125, 2264–2269.
  41. Naugler, W.E.; Sakurai, T.; Kim, S.; Maeda, S.; Kim, K.; Elsharkawy, A.M.; Karin, M. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 2007, 317, 121–124, Erratum in Science 2009, 326, 1346.
  42. Falleti, E.; Fabris, C.; Toniutto, P.; Fontanini, E.; Cussigh, A.; Bitetto, D.; Fumolo, E.; Fornasiere, E.; Bragagnini, W.; Pinato, D.J.; et al. Interleukin-6 polymorphisms and gender: Relationship with the occurrence of hepatocellular carcinoma in patients with end-stage liver disease. Oncology 2009, 77, 304–313.
  43. Stein, B.; Yang, M.X. Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF-kappa B and C/EBP beta. Mol. Cell. Biol. 1995, 15, 4971–4979.
  44. Galdiero, M.R.; Garlanda, C.; Jaillon, S.; Marone, G.; Mantovani, A. Tumor associated macrophages and neutrophils in tumor progression. J. Cell. Physiol. 2013, 228, 1404–1412.
  45. Mantovani, A.; Sozzani, S.; Locati, M.; Allavena, P.; Sica, A. Macrophage polarization: Tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002, 23, 549–555.
  46. Yang, W.; Lu, Y.; Xu, Y.; Xu, L.; Zheng, W.; Wu, Y.; Li, L.; Shen, P. Estrogen represses hepatocellular carcinoma (HCC) growth via inhibiting alternative activation of tumor-associated macrophages (TAMs). J. Biol. Chem. 2012, 287, 40140–40149.
  47. Sharma, B.R.; Kanneganti, T.D. NLRP3 inflammasome in cancer and metabolic diseases. Nat. Immunol. 2021, 22, 550–559.
  48. Swanson, K.V.; Deng, M.; Ting, J.P. The NLRP3 inflammasome: Molecular activation and regulation to therapeutics. Nat. Rev. Immunol. 2019, 19, 477–489.
  49. Wei, Q.; Mu, K.; Li, T.; Zhang, Y.; Yang, Z.; Jia, X.; Zhao, W.; Huai, W.; Guo, P.; Han, L. Deregulation of the NLRP3 inflammasome in hepatic parenchymal cells during liver cancer progression. Lab. Investig. 2014, 94, 52–62.
  50. Wei, Q.; Guo, P.; Mu, K.; Zhang, Y.; Zhao, W.; Huai, W.; Qiu, Y.; Li, T.; Ma, X.; Liu, Y.; et al. Estrogen suppresses hepatocellular carcinoma cells through ERβ-mediated upregulation of the NLRP3 inflammasome. Lab. Investig. 2015, 95, 804–816.
  51. Naamneh Elzenaty, R.; du Toit, T.; Flück, C.E. Basics of androgen synthesis and action. Best Pract. Res. Clin. Endocrinol. Metab. 2022, 36, 101665.
  52. Fanelli, F.; Baronio, F.; Ortolano, R.; Mezzullo, M.; Cassio, A.; Pagotto, U.; Balsamo, A. Normative Basal Values of Hormones and Proteins of Gonadal and Adrenal Functions from Birth to Adulthood. Sex. Dev. 2018, 12, 50–94.
  53. Montgomery, E.J.; Xing, E.; Campbell, M.J.; Li, P.K.; Blachly, J.S.; Tsung, A.; Coss, C.C. Constitutively Active Androgen Receptor in Hepatocellular Carcinoma. Int. J. Mol. Sci. 2022, 23, 13768.
  54. Ma, W.L.; Hsu, C.L.; Wu, M.H.; Wu, C.T.; Wu, C.C.; Lai, J.J.; Jou, Y.S.; Chen, C.W.; Yeh, S.; Chang, C. Androgen receptor is a new potential therapeutic target for the treatment of hepatocellular carcinoma. Gastroenterology 2008, 135, 947–955.e5, Erratum in Gastroenterology 2008, 135, 1805. Ma, Cheng-Lung .
  55. Zhang, H.; Li, X.X.; Yang, Y.; Zhang, Y.; Wang, H.Y.; Zheng, X.F.S. Significance and mechanism of androgen receptor overexpression and androgen receptor/mechanistic target of rapamycin cross-talk in hepatocellular carcinoma. Hepatology 2018, 67, 2271–2286.
  56. Feng, H.; Cheng, A.S.; Tsang, D.P.; Li, M.S.; Go, M.Y.; Cheung, Y.S.; Zhao, G.J.; Ng, S.S.; Lin, M.C.; Yu, J.; et al. Cell cycle-related kinase is a direct androgen receptor-regulated gene that drives β-catenin/T cell factor-dependent hepatocarcinogenesis. J. Clin. Investig. 2011, 121, 3159–3175.
  57. Wang, S.H.; Chen, P.J.; Yeh, S.H. Gender disparity in chronic hepatitis B: Mechanisms of sex hormones. J. Gastroenterol. Hepatol. 2015, 30, 1237–1245.
  58. Di Maio, M.; Daniele, B.; Pignata, S.; Gallo, C.; De Maio, E.; Morabito, A.; Piccirillo, M.C.; Perrone, F. Is human hepatocellular carcinoma a hormone-responsive tumor? World J. Gastroenterol. 2008, 14, 1682–1689.
  59. Nevola, R.; Delle Femine, A.; Rosato, V.; Kondili, L.A.; Alfano, M.; Mastrocinque, D.; Imbriani, S.; Perillo, P.; Beccia, D.; Villani, A.; et al. Neoadjuvant and Adjuvant Systemic Therapies in Loco-Regional Treatments for Hepatocellular Carcinoma: Are We at the Dawn of a New Era? Cancers 2023, 15, 2950.
  60. Lee, C.M.; Lu, S.N.; Changchien, C.S.; Yeh, C.T.; Hsu, T.T.; Tang, J.H.; Wang, J.H.; Lin, D.Y.; Chen, C.L.; Chen, W.J. Age, gender, and local geographic variations of viral etiology of hepatocellular carcinoma in a hyperendemic area for hepatitis B virus infection. Cancer 1999, 86, 1143–1150.
  61. Wang, S.H.; Yeh, S.H.; Lin, W.H.; Wang, H.Y.; Chen, D.S.; Chen, P.J. Identification of androgen response elements in the enhancer I of hepatitis B virus: A mechanism for sex disparity in chronic hepatitis B. Hepatology 2009, 50, 1392–1402.
  62. Yang, W.J.; Chang, C.J.; Yeh, S.H.; Lin, W.H.; Wang, S.H.; Tsai, T.F.; Chen, D.S.; Chen, P.J. Hepatitis B virus X protein enhances the transcriptional activity of the androgen receptor through c-Src and glycogen synthase kinase-3beta kinase pathways. Hepatology 2009, 49, 1515–1524.
  63. Zheng, B.; Zhu, Y.J.; Wang, H.Y.; Chen, L. Gender disparity in hepatocellular carcinoma (HCC): Multiple underlying mechanisms. Sci. China Life Sci. 2017, 60, 575–584.
  64. Wang, S.H.; Yeh, S.H.; Lin, W.H.; Yeh, K.H.; Yuan, Q.; Xia, N.S.; Chen, D.S.; Chen, P.J. Estrogen receptor α represses transcription of HBV genes via interaction with hepatocyte nuclear factor 4α. Gastroenterology 2012, 142, 989–998.e4.
  65. Lai, J.J.; Lai, K.P.; Zeng, W.; Chuang, K.H.; Altuwaijri, S.; Chang, C. Androgen receptor influences on body defense system via modulation of innate and adaptive immune systems: Lessons from conditional AR knockout mice. Am. J. Pathol. 2012, 181, 1504–1512.
  66. Nevola, R.; Beccia, D.; Rosato, V.; Ruocco, R.; Mastrocinque, D.; Villani, A.; Perillo, P.; Imbriani, S.; Delle Femine, A.; Criscuolo, L.; et al. HBV Infection and Host Interactions: The Role in Viral Persistence and Oncogenesis. Int. J. Mol. Sci. 2023, 24, 7651.
  67. Poynard, T.; Ratziu, V.; Charlotte, F.; Goodman, Z.; McHutchison, J.; Albrecht, J. Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis c. J. Hepatol. 2001, 34, 730–739.
  68. Kanda, T.; Steele, R.; Ray, R.; Ray, R.B. Hepatitis C virus core protein augments androgen receptor-mediated signaling. J. Virol. 2008, 82, 11066–11072.
  69. Li, P.; Du, Q.; Cao, Z.; Guo, Z.; Evankovich, J.; Yan, W.; Chang, Y.; Shao, L.; Stolz, D.B.; Tsung, A.; et al. Interferon-γ induces autophagy with growth inhibition and cell death in human hepatocellular carcinoma (HCC) cells through interferon-regulatory factor-1 (IRF-1). Cancer Lett. 2012, 314, 213–222.
  70. Ulitzky, L.; Lafer, M.M.; KuKuruga, M.A.; Silberstein, E.; Cehan, N.; Taylor, D.R. A New Signaling Pathway for HCV Inhibition by Estrogen: GPR30 Activation Leads to Cleavage of Occludin by MMP-9. PLoS ONE 2016, 11, e0145212.
  71. Baecker, A.; Liu, X.; La Vecchia, C.; Zhang, Z.F. Worldwide incidence of hepatocellular carcinoma cases attributable to major risk factors. Eur. J. Cancer Prev. 2018, 27, 205–212.
  72. Gupta, A.; Das, A.; Majumder, K.; Arora, N.; Mayo, H.G.; Singh, P.P.; Beg, M.S.; Singh, S. Obesity is Independently Associated With Increased Risk of Hepatocellular Cancer-related Mortality: A Systematic Review and Meta-Analysis. Am. J. Clin. Oncol. 2018, 41, 874–881.
  73. Raff, E.J.; Kakati, D.; Bloomer, J.R.; Shoreibah, M.; Rasheed, K.; Singal, A.K. Diabetes Mellitus Predicts Occurrence of Cirrhosis and Hepatocellular Cancer in Alcoholic Liver and Non-alcoholic Fatty Liver Diseases. J. Clin. Transl. Hepatol. 2015, 3, 9–16.
  74. Marengo, A.; Rosso, C.; Bugianesi, E. Liver Cancer: Connections with Obesity, Fatty Liver, and Cirrhosis. Annu. Rev. Med. 2016, 67, 103–117.
  75. Al-Hussaniy, H.A.; Alburghaif, A.H.; Naji, M.A. Leptin hormone and its effectiveness in reproduction, metabolism, immunity, diabetes, hopes and ambitions. J. Med. Life 2021, 14, 600–605.
  76. Polyzos, S.A.; Kountouras, J.; Zavos, C.; Deretzi, G. The potential adverse role of leptin resistance in nonalcoholic fatty liver disease: A hypothesis based on critical review of the literature. J. Clin. Gastroenterol. 2011, 45, 50–54.
  77. Rotundo, L.; Persaud, A.; Feurdean, M.; Ahlawat, S.; Kim, H.S. The Association of leptin with severity of non-alcoholic fatty liver disease: A population-based study. Clin. Mol. Hepatol. 2018, 24, 392–401.
  78. Saxena, N.K.; Sharma, D.; Ding, X.; Lin, S.; Marra, F.; Merlin, D.; Anania, F.A. Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells. Cancer Res. 2007, 67, 2497–2507.
  79. Shen, M.; Shi, H. Estradiol and Estrogen Receptor Agonists Oppose Oncogenic Actions of Leptin in HepG2 Cells. PLoS ONE 2016, 11, e0151455.
  80. Choi, H.M.; Doss, H.M.; Kim, K.S. Multifaceted Physiological Roles of Adiponectin in Inflammation and Diseases. Int. J. Mol. Sci. 2020, 21, 1219.
  81. Xu, A.; Wang, Y.; Keshaw, H.; Xu, L.Y.; Lam, K.S.; Cooper, G.J. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J. Clin. Investig. 2003, 112, 91–100.
  82. Manieri, E.; Herrera-Melle, L.; Mora, A.; Tomás-Loba, A.; Leiva-Vega, L.; Fernández, D.I.; Rodríguez, E.; Morán, L.; Hernández-Cosido, L.; Torres, J.L.; et al. Adiponectin accounts for gender differences in hepatocellular carcinoma incidence. J. Exp. Med. 2019, 216, 1108–1119.
  83. Nishizawa, H.; Shimomura, I.; Kishida, K.; Maeda, N.; Kuriyama, H.; Nagaretani, H.; Matsuda, M.; Kondo, H.; Furuyama, N.; Kihara, S.; et al. Androgens decrease plasma adiponectin, an insulin-sensitizing adipocyte-derived protein. Diabetes 2002, 51, 2734–2741.
  84. Diener, C.; Keller, A.; Meese, E. Emerging concepts of miRNA therapeutics: From cells to clinic. Trends Genet. 2022, 38, 613–626.
  85. Yamada, H.; Suzuki, K.; Ichino, N.; Ando, Y.; Sawada, A.; Osakabe, K.; Sugimoto, K.; Ohashi, K.; Teradaira, R.; Inoue, T.; et al. Associations between circulating microRNAs (miR-21, miR-34a, miR-122 and miR-451) and non-alcoholic fatty liver. Clin. Chim. Acta 2013, 424, 99–103.
  86. Khan, S.; Ayub, H.; Khan, T.; Wahid, F. MicroRNA biogenesis, gene silencing mechanisms and role in breast, ovarian and prostate cancer. Biochimie 2019, 167, 12–24.
  87. Morishita, A.; Oura, K.; Tadokoro, T.; Fujita, K.; Tani, J.; Masaki, T. MicroRNAs in the Pathogenesis of Hepatocellular Carcinoma: A Review. Cancers 2021, 13, 514.
  88. Morishita, A.; Iwama, H.; Fujihara, S.; Sakamoto, T.; Fujita, K.; Tani, J.; Miyoshi, H.; Yoneyama, H.; Himoto, T.; Masaki, T. MicroRNA profiles in various hepatocellular carcinoma cell lines. Oncol. Lett. 2016, 12, 1687–1692.
  89. Chen, P.J.; Yeh, S.H.; Liu, W.H.; Lin, C.C.; Huang, H.C.; Chen, C.L.; Chen, D.S.; Chen, P.J. Androgen pathway stimulates microRNA-216a transcription to suppress the tumor suppressor in lung cancer-1 gene in early hepatocarcinogenesis. Hepatology 2012, 56, 632–643.
  90. Liu, W.H.; Yeh, S.H.; Lu, C.C.; Yu, S.L.; Chen, H.Y.; Lin, C.Y.; Chen, D.S.; Chen, P.J. MicroRNA-18a prevents estrogen receptor-alpha expression, promoting proliferation of hepatocellular carcinoma cells. Gastroenterology 2009, 136, 683–693.
  91. Pandey, D.P.; Picard, D. miR-22 inhibits estrogen signaling by directly targeting the estrogen receptor alpha mRNA. Mol. Cell. Biol. 2009, 29, 3783–3790, Erratum in: Mol Cell Biol 2009, 29, 4873.
  92. Jiang, R.; Deng, L.; Zhao, L.; Li, X.; Zhang, F.; Xia, Y.; Gao, Y.; Wang, X.; Sun, B. miR-22 promotes HBV-related hepatocellular carcinoma development in males. Clin. Cancer Res. 2011, 17, 5593–5603.
  93. Sakurai, T.; He, G.; Matsuzawa, A.; Yu, G.Y.; Maeda, S.; Hardiman, G.; Karin, M. Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell 2008, 14, 156–165.
  94. Zhao, Q.; Li, T.; Qi, J.; Liu, J.; Qin, C. The miR-545/374a cluster encoded in the Ftx lncRNA is overexpressed in HBV-related hepatocellular carcinoma and promotes tumorigenesis and tumor progression. PLoS ONE 2014, 9, e109782.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Gastroenterology & Hepatology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Riccardo Nevola
,
Giovanni Tortorella
,
Valerio Rosato
,
Luca Rinaldi
,
Simona Imbriani
,
Pasquale Perillo
,
Davide Mastrocinque
,
Marco La Montagna
,
Antonio Russo
,
Giovanni Di Lorenzo
,
Maria Alfano
,
Maria Rocco
,
Carmen Ricozzi
,
Klodian Gjeloshi
,
Ferdinando Carlo Sasso
,
Raffaele Marfella
,
Aldo Marrone
,
Loreta Anesti Kondili
,
Nicolino Esposito
,
Ernesto Claar
,
Domenico Cozzolino
View Times: 508
Revisions: 3 times (View History)
Update Date: 21 Jul 2023
Table of Contents
    1000/1000
    Hot Most Recent
    ScholarVision Creations
    Feedback