H2S in Oncological Disorders and Non-Coding RNAs Regulation: History
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Contributor:
Rana A. Youness
,
Danira Ashraf Habashy
,
Nour Khater
,
Kareem Elsayed
,
Alyaa Dawoud
,
Sousanna Hakim
,
Heba Nafea
,
Carole Bourquin
,
Reham M. Abdel-Kader
,
Mohamed Z. Gad

H2S is colorless, flammable, and water-soluble gas with a characteristic smell of rotten eggs; it is now widely recognized as an endogenous biological mediator. Since its discovery, H2S has been found to have vital functions in various physiological and pathological conditions. Non-coding RNAs (ncRNAs) form a relatively recent class of post-transcriptional regulators that is widely expanding. Non-coding RNAs (ncRNAs) have been reported to play a dominating role in the regulation of the endogenous machinery system of H2S in several pathological contexts. A growing list of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are leading the way as upstream regulators for H2S biosynthesis in different mammalian cells during the development and progression of human diseases.

  • H2S
  • non-coding RNAs (ncRNAs)
  • regulation
  • cell cycle
  • apoptosis
  • angiogenesis
  • cancer

1. Introduction

Historically, hydrogen sulfide (H2S) has been a gas notorious for its noxious pungent odor of rotten eggs and for being identified as a toxic pollutant gas associated with several industries [1]. The identification of endogenous H2S in tissues has been reported in 1992, when Abe and Kimura reported on the endogenous production and signaling capacity of H2S as a neuromodulator [2].
The elucidation of its cellular signaling mechanisms led to the introduction of H2S into the family of gaseous signaling molecules known as gasotransmitters [3]. Until now, there have been three discovered gasotransmitters: nitric oxide (NO), identified in 1987, followed by discovery of carbon monoxide (CO) in 1990 and then the most recent member, H2S, in 1996 [4]. All the discovered gasotransmitters share a common set of characteristics, including regulated endogenous production, free permeation of cell membranes without transporters, and unique signaling function with certain interactions with cellular and molecular targets [3]. In addition, they have anti-inflammatory, anti-oxidant, anti-apoptotic, and cardioprotective activities. Yet, their point of difference is allocated in their endogenous production and their respective types of synthesizing enzymes, half-lives, and second messenger signaling [5].
H2S is colorless, flammable, and water-soluble gas with a characteristic smell of rotten eggs; it is now widely recognized as an endogenous biological mediator [6]. Similar to CO and NO, the old conventional thinking that all these gases are vicious and exert only detrimental influence on human health has gradually lost ground [7]. Since its discovery, H2S has been found to have vital functions in various physiological and pathological conditions [8][9][10][11]. Yet, its role in the malignant transformation process is still controversial and leads to a lot of puzzling conclusions. Moreover, unraveling H2S interactions within different tissues, its precise impact in different pathological conditions, and its interplay with other biochemical molecules and various signaling mediators is becoming even more complex [8]. It is worth noting that, recently, H2S has also been reported to be involved in the SARS-CoV-2 life cycle and associated symptoms [12], and others reported the protective role of H2S-releasing compounds in ameliorating SARS-CoV-2-associated lung endothelial barrier disruption [13].
Non-coding RNAs (ncRNAs) form a relatively recent class of post-transcriptional regulators that is widely expanding [14][15][16][17][18][19]. Recent work has redefined the perception of ncRNAs from ‘junk’ non-coding transcripts into functional regulatory mediators [20][21][22][23][24][25][26][27][28]. NcRNAs can regulate several cellular processes, such as chromatin re-modeling, post-transcriptional modifications, and the regulation of signal transduction pathways, through targeting several target mRNAs simultaneously [17][19][29][30]. Recently, the potential roles of ncRNAs in regulating H2S biosynthesis in several physiological and pathological contexts have been highlighted [31][32][33][34][35][36][37][38]. H2S and ncRNAs interact during the development and progression of several human diseases; therefore, their targeting can be of great therapeutic benefit [17]. It is also worth mentioning that miRNAs and lncRNAs are the dominating ncRNAs for regulating H2S biosynthesis in mammalian cells. However, this does not exclude the possibility that other ncRNAs are also involved in H2S biosynthesis regulation.
Most of the reported literature supports the pro-carcinogenic competence of endogenous H2S. Different oncogenic cascades have been drawn downstream for H2S, such as hastening of cell cycle progression, propagating anti-apoptotic signals and the induction of angiogenesis, thus supporting the novel concept of inhibiting H2S production as a promising strategy for cancer treatment [39].

2. Hastening of Cell Cycle

The cell cycle represents a series of highly regulated waves that control the transition of cells from the quiescent state (G0) to proliferative status and ensure the high conformity of the genetic transcript material [40]. Most adult mammalian cells are in the quiescent state, and their re-entry into the cell cycle requires the inactivation of the retinoblastoma protein (pRB) and the transcription of genes required for DNA replication and chromosome segregation [41]. Any disturbance in the regulation of cell cycle is a common feature in the development of human cancers [40]. A recent study reported that the knocking down of CSE in HCC cell lines induced G1/G0 phase arrest and decreased the cell population in S phase, while the cell population in S phase was induced via the administration of 100 µM of NaHS for 24 h [42]. NaHS is an inorganic sulfide salt that has been widely used as an H2S equivalent in many biological studies. Furthermore, NaHS has been widely used in studies investigating the role of exogenous H2S in cancer progression, as it rapidly releases H2S via simple hydrolysis under laboratory conditions [43]. Similarly, another study indicated that exogenous H2S (NaHS, 200–500 µM) served as a pro-proliferative factor that accelerates cell cycle progression in oral squamous cell carcinoma through the increased phosphorylation of Akt and extracellular signal-regulated kinase (ERK) [44]. Likewise, exogenous H2S picked up the pace of the cell cycle in HCT116 via another mechanism of action, where it induced the repression of the tumor suppressor protein (p21), one of the cyclin-dependent kinase (CDK) inhibitory proteins, and, thus, decreased the G0/G1 population and increased the cell population at the S phase [45].

3. Propagation of Anti-Apoptotic Signals

Apoptosis is a tightly nuanced cellular suicide program that is critical for the normal development and maintenance of tissue homeostasis in multi-cellular organisms. In cancer cells, apoptosis is suppressed, which is the main reason for the uncontrolled cellular proliferation and resistance to treatment [46]. The CSE/H2S pathway played a vital role in maintaining the cancerous behavior of hepatoma cells, and the inhibition of this pathway could significantly suppress the uncontrolled growth of hepatoma cells by stimulating mitochondrial apoptosis and suppressing cell growth signal transduction [47]. In the same way, another study reported that the treatment of PLC/PRF/5 hepatoma cells with 500 µM NaHS for 24 h markedly increased cellular viability and decreased the number of apoptotic cells [48]. In the same pattern, the exogenous application of 100–1000 µM NaHS for 10 min or the overexpression of CBS hindered apoptosis-induced 6-Hydroxydopamine in a human neuroblastoma cell line [49].

4. Induction of Angiogenesis

Angiogenesis, or the sprouting of new blood vessels from the existing vasculature, mediated by several growth factors, such as VEGF, EGF, IGF, and angiogenin [50], was reported to be a fundamental step in the process of metastasis [51]. A growing body of evidence highlights H2S as a vital stimulator of the malignant transformation process, starting from its support for the tumor cellular proliferation and ending with its invigoration of angiogenesis [52]. Recent studies indicate that H2S possesses pro-angiogenic effects mainly by increasing VEGF expression [53][54]. In colon and ovarian cancers, CBS knockdown reduces the metastatic potential of cancer cells and decreases the number of sprouted blood vessels, thus resulting in the attenuation of tumor growth [55][56]. Taken together, these results support the possibility of utilizing CBS, CSE and 3-MST as potential molecular targets for cancer treatment.

5. Colon Cancer

Also Szabo group highlighted that CBS is selectively upregulated in colon cancer tissues compared with non-malignant colonic epithelial tissues [56][57]. Through a series of studies involving the knocking in/out of CBS expression or CBS activity (allosteric activation via SAM or inhibition using amino-oxyacetic acid (AOAA) in the HCT116 colon cancer cell line, it was validated that CBS encourages tumor cell advancement [56]. Additionally, several human colon cancer cells displayed elevated CBS expression in comparison to normal non-malignant colon cancer cell lines (NCM356). In 2013, Szabo et al. reported that CBS silencing or inhibition resulted in the suppression of cell proliferation, as well as migration and invasion in HCT116 cells [56]. In line with these findings, SAM, an allosteric activator of CBS, was tested at low concentrations in HCT116, and it resulted in an increase in cell proliferation [58].
The induction of the Akt/PI3K signaling pathway is likely to trigger the pro-proliferative and migratory effects of CBS-synthesized H2S. These findings were validated in an in vivo model, where the growth rate in mice bearing xenografts of either HCT116 cells or patient-derived tumor tissue were significantly reduced following the silencing of CBS expression and/or inhibition of CBS expression via AOAA [59]. In addition, AOAA reduced the metastatic spread of HCT116 cells from the cecum to the liver in an orthotopic xenograft model of nude mice [60]. A recent study conducted by Guo et al. 2021 showed that the stable knockout of CBS using the CRISPR/Cas9 system in colon cancer cells caused the suppression of invasion and metastasis of cells. This study also showed that CBS knockdown reduced the expression of angiogenesis-related proteins such as VEGF [61].
Chen et al. studied the effects of miRNAs on the acquired resistance of 5-fluorouracil. The study revealed that the expression of miR-215-5p is altered following the knockdown of CBS, resulting in the increased sensitivity of HCT116 cells to 5-flurouracil. This effect was also noticed in an in vivo model [62]. Potential targets of miR-215-5p include epiregulin (EREG) and thymidylate synthetase (TYMS), whose expressions were attenuated via the inhibition of H2S synthesis, contributing to the reversal of acquired resistance to 5-flurouracil in HCT116 cell lines [62]. Regarding CSE, Olah et al. highlighted that in most colon cancer patients, CSE expression was quite low in both human biopsies. With respect to 3-MST, it displayed variable levels of expression. Nearly 50% of the individual sample pairs were of a higher expression level in the tumor compared to the normal counterparts, while the rest of the samples (50%) showed a low expression profile [63]. It is worth mentioning that upon performing literature screening, neither CSE nor 3MST regulation by ncRNAs in colon cancer had been previously investigated.

6. Breast Cancer

Several studies have shown that human breast cancer tissues and cells lines (MDA-MB-468, MCF-7, and Hs578T) reveal the marked overexpression of CBS, CSE, and 3MST compared to normal breast cells [31][64][65]. Recently, the research group has highlighted the potential regulation of CBS and CSE in breast cancer cell lines by miR-4317 [31] and miR-939-5p [66][67]. It is worth mentioning that, recently, miR-548 and miR-193 have been found by the research group to simultaneously target the three synthesizing enzymes in breast cancer: CBS, CSE and 3MST (Table 1) [64][68].
Digging deeper into the intricate crosstalk and potential interplays between H2S and different types of ncRNAs, the research group investigated the role of the lncRNA MALAT-1 in regulating STAT-3-regulated CSE in BC. The results show that upon the knockdown of MALAT-1, a marked repression of STAT-3 and CSE was observed, thereby highlighting MALAT-1 as a novel upstream lncRNA regulating the STAT-3/CSE/ H2S axis in breast cancer [69]. Table 1 shows a summary of most of the ncRNAs (miRNAs or lncRNAs) regulating H2S-synthesizing enzymes in different pathological disorders.

7. Ovarian Cancer

Similar to results of colon and breast cancers, Bhattacharyya et al. have found that CBS is overexpressed in primary epithelial ovarian cancer human biopsies and cell lines, particularly in serous carcinoma, the most common histologic variant. The majority of ovarian cancer cells showed high CBS expression (both on the mRNA and protein levels) compared to normal ovarian surface epithelial cells [55]. In the same study, the authors also studied the regulatory role of CBS-derived H2S in modulating ovarian cancer cell proliferation, migration, and invasion in vitro and in vivo. In the in vitro model, a variety of genetically mediated stable silencing and pharmacological inhibition of CBS were used where either the silencing of CBS or CBS inactivation by AOAA was found to inhibit cellular viability and proliferation [55]. In the in vivo models, the silencing of CBS led to a significant decrease in tumor weight and the number of tumor nodules, while the inhibition of peritumor angiogenesis was confirmed to cause a marked reduction in CD31 staining [55]. It is worth mentioning that upon performing literature screening, the regulation of H2S-synthesizing enzymes by ncRNAs in ovarian cancer had not been previously investigated.

8. Melanoma

Penza et al. [70] evaluated the involvement of the H2S pathway in melanoma. An interesting study was performed involving more than 100 human samples that showed that elevated CSE expression increased from nevi to primary melanoma, decreased in tissue metastases, and was absent in lymph node metastases. On the other hand, the screening of the CBS expression level in the same cohort of patients revealed that CBS was absent in dysplastic nevi. Positive CBS expression was found in only 25% of the primary melanomas analyzed. Therefore, as opposed to other types of cancer reviewed in this research, CBS does not appear to play an dominant role in human melanoma. It is also worth noting that 3-MST expression showed a variable alteration in the analyzed human specimens (from nevi to metastasis) [70]. It is also worth noting that upon performing literature screening, H2S-synthesizing enzymes regulation by ncRNAs in melanoma had not been previously investigated.

9. Liver Cancer

Jia et al. [71] showed that CBS protein was highly expressed in the human hepatoma cell lines HepG2 and SMMC-7721. This observation paved the way for the idea that CBS/H2S is involved in HCC proliferation. This hypothesis was validated upon the silencing of the CBS using CBS siRNAs and the inactivation of CBS activity using AOAA, which evidently repressed the proliferation of HCC cell lines. Also, CBS siRNAs induced the apoptosis of SMMC-7721 cells, revealing the involvement of the CBS-induced H2S production in regulating hepatoma cell proliferation. In addition, an increase in the Bax/Bcl ratio and a significant upregulation of caspase-3 and PARP activities were evident following CBS knockdown [71].

10. Lung Cancer

Significantly higher protein levels of CBS, CSE, and 3-MST were detected in human lung adenocarcinoma samples compared to normal counterparts. Similarly, elevated expression of CBS, CSE, and 3-MST and H2S production were also reported in multiple lung adenocarcinoma cell lines (A549, H522 and H1944) compared to non-malignant lung epithelial cells (BEAS 2B) [72].

11. Bladder Cancer

The expression of H2S-producing enzymes in human bladder cancer tissues compared to their normal counterparts was investigated. Our results showed that H2S levels, as well as CBS, CSE, and 3-MST expression, were higher in bladder cancer biopsies compared to their normal counterparts. Notably, the expression of all three enzymes was correlated to different stages of bladder cancer [73]. Another study showed that the apoptosis of bladder cancer cells was heightened after the inhibition of H2S production by propargylglycine (PAG) and inhibited upon adding exogenous H2S. This was validated in in vitro, as well as in vivo, models. The stimulation of the Erk1/2 signaling pathway and the blockade of mitochondrial apoptosis were suggested as the probable mechanisms behind these results [74]. Exogenous H2S supplementation has also been shown to affect bladder cancer cells. It was found that preconditioning cells with sodium hydrosulfide (NaHS) boosted cells’ proliferation and invasion capacity. This was evident in the expression of matrix metalloproteinases (MMP) 2 and 9, which are crucial for the digestion of collagen IV and hydrolysis of extracellular matrix during invasion, as they increased in a dose-dependent manner after the treatment of bladder cancer cells with NaHS [75].

12. Leukemia

CBS was found to be elevated in bone marrow mononuclear cells isolated from newly diagnosed children with CML compared to age- and gender-matched control groups. Meanwhile, the CSE and 3-MST levels showed no significant differences between the two groups. At the in vitro level, in CML-derived K562 cells, the upregulation of CBS expression was demonstrated. CSE and 3-MST displayed no significant differences in their expression levels [76]. The silencing or pharmacological inhibition of CBS using AOAA induced a decrease in the cell proliferation of both K562 cells and bone marrow mononuclear cells from CML patients. This was mediated via the mitochondria-related apoptosis pathway [76].

13. Multiple Myeloma

The CBS expression level was significantly higher in patients with multiple myeloma than healthy donors [77]. The pharmacologic inhibition of H2S production using AOAA successfully inhibited the proliferation of the U266 myeloma cell line in a concentration-dependent manner. Exogenous NaHS has a pro-tumorigenic effect on U266 cells by enhancing cell cycle progression, which was diminished by using AOAA. AOAA treatment resulted in a decrease in the expression of anti-apoptotic Bcl-2 and an increase in caspase-3, thus promoting apoptosis [77].
Table 1. Non-coding RNAs regulating H2S-synthesizing enzymes.
H2S Synthesizing Enzyme miRNA LncRNA Cell Lines Investigated
CBS miR-4317 [31]
miR-6852 [78]
miR-21 [32]
miR-376a [79]
miR-125b-5p [80]
miR-203 [81]
miR-215-5p [62]
miR-939-5p [38]
miR-548 [64]
miR-193 [68]		 LINC00336 [78]
lncRNA CBSLR [82]
LncRNA SNHG1 [79]		 MDA-MB-231
MCF-7
A549
SPC-A-1
MGECs
HCMIEC/D3
PC-12
SH-SY5Y
HT-29
DLD-1
MKN45
MKN28
CSE miR-4317 [31]
miR-21 [32]
miR-216a [83]
miR-186 [84]
miR-30a-5p [85]
miR-328-3p [86]
miR-30b-5p [87]
miR-22 [88]
miR-939-5p [38]
miR-548 [64]
miR-193 [68]		 LncRNA Oprm1 [87]
lncRNA MALAT-1 [69]		 MDA-MB-231
MCF-7
HEK-293FT
Primary cultured neonatal cardiomyocytes
Mouse Airway Epithelial Cells (MAECs)
THP-1 macrophages
Vascular Smooth Muscle Cells (SMCs)
3-MST miR-548 [64]
miR-193 [68]		 Not available MDA-MB-231

This entry is adapted from the peer-reviewed paper 10.3390/ncrna10010007

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