Phytochemicals Modulate lncRNAs and Carbonic Anhydrases in Cancer: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Reza Zolfaghari Emameh.

Long non-coding RNAs (lncRNAs) are classified as a group of transcripts that regulate various biological processes, such as RNA processing, epigenetic control, and signaling pathways. According to recent studies, lncRNAs are dysregulated in cancer and play an important role in cancer incidence and spreading. There is also an association between lncRNAs and the overexpression of some tumor-associated proteins, including carbonic anhydrases II, IX, and XII (CA II, CA IX, and CA XII). Therefore, not only CA inhibition but also lncRNA modulation, could represent an attractive strategy for cancer prevention and therapy. Experimental studies have suggested that herbal compounds regulate the expression of many lncRNAs involved in cancer, such as HOTAIR (HOX transcript antisense RNA), H19, MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), PCGEM1 (Prostate cancer gene expression marker 1), PVT1, etc. These plant-derived drugs or phytochemicals include resveratrol, curcumin, genistein, quercetin, epigallocatechin-3-galate, camptothecin, and 3,3'-diindolylmethane. More comprehensive information about lncRNA modulation via phytochemicals would be helpful for the administration of new herbal derivatives in cancer therapy. In this review, we describe the state-of-the-art and potential of phytochemicals as modulators of lncRNAs in different types of cancers.

  • phytochemicals
  • long non-coding RNA
  • carbonic anhydrase
  • cancer
  • modulator

1. Introduction

Phytochemicals are non-nutritive chemical components taken from various vegetables, fruits, beverages, and other green plants. Generally, the mechanism of action of these compounds occurs through the simulation of hormones, while they are known by their anti-oxidant and anti-inflammatory activities in cells [37,38,39,40][1][2][3][4]. To date, many phytochemicals have been identified and several are considered potential drugs due to their anticancer properties. They can be used as single chemopreventive drugs or synergistically with other routine anticancer drugs. This kind of anticancer drug administration can improve the efficacy of the treatment strategy, and optimally, with minimal or no side effects [41,42][5][6]. It has been suggested that phytochemicals act through the modulation of different signaling pathways via the regulation of significant molecular targets [43,44][7][8]. 

2. Biogenesis of lncRNA

After the discovery of coding and non-coding parts of the genome, it was suggested that non-coding sections may play an important role in cellular activities [45][9]. Furthermore, recent findings have suggested that lncRNAs function in various cancers, where their contribution is based on developmental and tissue specific expression patterns [46,47,48,49,50,51,52,53,54][10][11][12][13][14][15][16][17][18]. Both coding and non-coding genes carry genetic information with different functions. According to their location in the genome, lncRNAs can be divided into four groups: (1) the intergenic lncRNAs, which are located between two genes; (2) the sense or antisense lncRNAs, which may overlap with an exon of another transcript in the same or opposite direction; (3) the intronic lncRNAs, which reside within an intron and do not overlap with any exon; and (4) the processed transcripts, which reside in a locus where none of the transcript has an ORF and thus, do not fit into any other categories because of structural complexity (Figure 1).
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Figure 1.
 The flow of genetic information encoding for mRNA and long non-coding RNA (lncRNA).
Three major properties of this RNA molecule were identified: (1) it might have or does not have an ORF for coding more than 100 amino acids; (2) there is no need for this section to produce a protein, but is still functional [56][19] and ; (3) it can contain both coding and non-coding domains [57,58,59][20][21][22].

3. Modulation of lncRNA by phytochemicals

lncRNAs are considered great targets for anticancer studies due to their potential tumor suppressor abilities. Several studies have suggested that the modulation of lncRNAs with various phytochemicals could be a novel option in cancer therapy. It has been clearly indicated that these lncRNAs are regulated by defined phytochemicals (Figure 2).
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Figure 2. Regulation of long non-coding RNAs (lncRNAs) by natural compounds and their inhibition effects on cell (A) apoptosis, (B) proliferation, (C) migration, and (D) invasion. The inhibition relationships are denoted as red stop symbols, whereas positive interactions are denoted as normal blue arrows. CUR: Curcumin, GEN: Genistein, RSV: Resveratrol, ECGC: Epigallocatechin-3-gallate, CPT: Camptothecin, DIM: 3,3-diindolylmethane, QUE: Quercetin. The blue arrows show the modulation roles of phytochemicals, the red arrows show the induction role of phytochemicals, and the T bars show the inhibition role of phytochemicals on the lncRNAs.

4. Camptothecin (CPT)

Camptothecin (CPT, C20H16N2O4) is an alkaloid derived from a Chinese tree Camptotheca acuminate (happy tree). CPT has an inhibitory role in topoisomerase I and possesses antitumor activity [115,116,117][23][24][25]. CPT was demonstrated to suppress hypoxia-inducible factor 1 alpha (HIF-1α) -antisense RNA 1 in different human cancer types [77,106,115][26][27][23]. CPT also induces apoptosis in cardiovascular and kidney carcinomas, which results in an enhancement of the expression of antisense lncRNA. In another study, CPT treatment was shown to regulate the expression of lncRNA HIF-1α synergically with miR-17-5-p and miR-155 [78][28]. CPT has the ability to reduce CA IX expression in the cancer zone through the inhibition of angiogenesis and hypoxia. CPT has been conjugated to a linear, cyclodextrin-polyethylene glycol (CD-PEG) copolymer to form CRLX101 as a nanoparticle-drug conjugate (NDC). The conjugation step revealed that CRLX101 was more efficient than CPT in terms of the induction of apoptosis and supression of angiogenesis [118,119,120,121][29][30][31][32] (Table 21).
Table 21.
 Long non-coding RNAs (lncRNAs) and carbonic anhydrases (CAs) affected by phytochemicals.
Phytochemicals lncRNAs Carbonic Anhydrases (CAs) Ref
Camptothecin (CPT) HIF-1α CA IX [118,119,120,121][29][30][31][32]
Curcumin GAS5, HOTAIR, H19, AF086415, AK095147, RP1-179N16.3, MUDENG, AK056098, AK294004 CA II, CA IX, CA XII [134,135,136,137,138,139][33][34][35][36][37][38]
3,3′-diindolylmethane (DIM) PCGEM1, FOXM1 CA I, II, IV, VII [145][39]
Epigallocatechin-3-galate (ECGC) AT102202 CA II, IX [155,156][40][41]
Genistein HOTAIR CA II [164,165,166][42][43][44]
Quercetin DBH-AS1 CA I, II, III, IV, XII, XIV [169,170,171,172][45][46][47][48]
Resveratrol PCGEM1, PRNCR1, PCAT29, AK001796, MALAT1, u-Eleanor, LINC00978 CA I‒XV [135,184][34][49]

5. Curcumin

Curcumin (diferul[84]oylmethane) (C21H20O6 or C21H20O6) is a polyphenol derived from a perennial herbaceous plant, Curcuma longa [122][50]. This spicy yellow powder is used as an anti-inflammatory, antimicrobial, and antioxidant in traditional Asian medicine [123,124][51][52]. Curcumin acts as a chemopreventive and chemotherapeutic drug against various types of tumors, and is an important lncRNA regulator in cancers [125][53]. Petric et al. have shown that curcumin has an inhibitory effect on some oncogenic signaling pathways, including NF-kB, and induces apoptotic processes in breast cancer [38][2]. In another study, curcumin inhibited the overexpression of GAS5 in lung cancer by affecting signaling pathways, such as NF-kB, STAT3, and PI3K/Akt, to suppress tumor cell proliferation [126][54]. Curcumin also caused the modulation of tumor suppressor HOTAIR in pancreatic cancer [13][55], prostate cancer [88][56], hepatocellular carcinoma (HCC) [84[57][58],86], nasopharyngeal carcinoma (NPC) [81][59], breast cancer [87][60], lung cancer [80][61], and renal cancer [62,84,85,86,87,104,127][62][57][63][58][60][64][65]. It seems that the upregulation of HOTAIR has a controversial effect in terms of the occurrence of different cancer types and response to therapy methods, so radioresistance in breast cancer is enhanced by upregulated HOTAIR [87][60]. In addition, the expression level of HOTAIR is higher in renal cell carcinoma in comparison with normal kidney cells and a correlation has been shown between the upregulation of HOTAIR and distant metastasis in renal cell carcinoma malignancy [128][66]. Therefore, curcumin acts as a HOTAIR modulator, which consequently modulates the miR-19/PTEN/AKT/p53 axis in cancers [129][67].

6. 3,3′-diindolylmethane (DIM)

3,3′-Diindolylmethane (DIM, C17H14N2) is a known phytochemical compound derived from indole-3-carbinol (I3C) [140][68]. It is found in cruciferous vegetables like broccoli, cabbage, and kale [141][69]. DIM has an impact on signaling pathways and can regulate cell division, apoptosis, and angiogenesis in cancer cells [142][70]. It has been demonstrated that DIM inhibits PCGEM1 expression and induces apoptosis in prostate cancer [103][71]. Moreover, it has been observed that DIM indirectly suppresses the Akt/FOXM1 signaling cascade by regulating FOXM1 gene expression [143][72]. FOXM1 regulates various lncRNAs in some carcinomas [144][73]. Bioresponse formulated 3,3′-diindolylmethane (BR-DIM) decreases androgen receptor (AR) variants and AR3 expression in prostate cancer [103][71]. A study revealed that the combination of indolin-based compounds with sulfonamides can inhibit CA I, II, IV, and VII [145][39] (Table 21).

7. Epigallocatechin-3-galate (EGCG)

Epigallocatechin (EGCG, C15H14O7) is a known polyphenol flavonoid derived from almond and green tea [146,147,148,149,150,151][74][75][76][77][78][79]. This compound regulates the expression of non-coding RNAs in tumors and has notable anticancer, anti-inflammatory, and antioxidant features [38][2]. EGCG modulates various signaling pathways, such as NF-kB, MAPK, Akt, PI3K, PTEN, and mTORC1, as well as the expression of the estrogen receptor (ER) [152,153,154][80][81][82]. It has been shown that EGCG suppresses a lncRNA, AT102202, which downregulates the expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) in human hepatocytes, leading to the uptake of cholesterol by the liver [70][83]. A study showed that polyphenol Epigallocatechin upregulates CA IX in breast cancer cells, which may possess strong antioxidative and antiapoptotic properties [155][40]. It has also been demonstrated that EGCG as a content of flavonoids in green tea has a suppression effect on CA II [156][41] (Table 21).

8. Genistein

Genistein (C15H10O5), a dietary soy isoflavone, is another phytochemical compound with in vitro and in vivo antitumor effects [157][84]. It has shown some anti-proliferation effects on many types of human cancers, such as breast, renal, and prostate cancers [38,66,82,158,159,160][2][85][86][87][88][89]. Genistein modulates the expression level of HOTAIR in breast cancer, which consequently modulates the activity of the PI3K/Akt signaling pathway [161][90]. Genistein suppresses the progression of renal cancer by inhibiting HOTAIR [66][85]. It was found that the miR-141 expression was upregulated, while the HOTAIR expression was downregulated, by genistein in cancer cells [157][84]. In prostate cancer, genistein reduced the HOTAIR and miR-34a expression synergically. Another study also suggested that genistein has antitumor effects in colorectal cancer by affecting HOTAIR [162][91]. In addition, genistein induces apoptosis in cancer cells, including breast, prostate, gastric, lung, pancreatic, melanoma, and renal cancers, by inhibiting several signaling pathways, such as Wnt and Akt [82,163][86][92]. The decreased expression of HOTAIR leads to apoptosis, which has been induced by genistein in multiple types of cancer [88][56]. In this case, most studies considered the correlation between phyto-isoflavones and -oestrogens in cervix, ovariectomy, uterus, and liver cancers through the modulatory effect of genistein on CA II expression [164,165,166][42][43][44] (Table 21).

9. Quercetin

Quercetin (C15H10O7) is a polyphenolic flavonoid with chemopreventive properties. This dietary antioxidant is derived from several plants and fruits, such as red grapes, broccoli, and some berries. Quercetin downregulated the expression of DBH-AS1 in hepatocellular carcinoma through its antiproliferative and antioxidant activities [71,72,73][93][94][95]. It was reported that quercetin acts as an inhibitor in different signaling pathways like Akt/mTOR/P70S6K and PI3K/AkT [97,167,168][96][97][98]. Most studies have confirmed the inhibition activity of quercetin on CA isoforms, including CA I, II, III, IV, XII, and XIV [169,170,171][45][46][47]. Recently, quercetin-modified metal–organic frameworks (Zr-MOF-QU) as the novel type of Zr-MOF nanoparticles have shown excellent efficiency for CA IX inhibition in tumor cells [172][48] (Table 21). Zr-MOF-QU seems to be used successfully in radiotherapy.

10. Resveratrol

Resveratrol (3,4′,5 tri-hydroxystilbene) (C14H12O3) is a natural polyphenol compound found in various plants and herbs, including blueberries, raspberries, mulberries, and the skin of grapes [173][99]. Resveratrol has anti-inflammatory and antiproliferative properties, as well as antitumor effects on various human cancers [93[100][101],174], including prostate [113,175][102][103], thyroid [176][104], colorectal [177[105][106],178], breast [179[107][108],180], lung [181[109][110],182], and bladder cancers [93,95,111,113,183][100][111][112][102][113]. Resveratrol inhibits the AR signaling pathway in prostate cancer by affecting PCGEM1 and PRNCR1 [107,108,109,110][114][115][116][117]. Another prostate cancer study revealed that resveratrol is a reverse potent stimulator in the reduction of PCAT29 expression induced by a cancer cell line [175][103]. Synergistic growth inhibition activity of resveratrol and AK001796 has been demonstrated in lung cancer [14][118]. There is also evidence that the treatment of lung cancer with resveratrol results in the downregulation of AK001796 expression. Studies have revealed that polyphenol resveratrol could inhibit CA I‒XV in cancers, so CA II was inhibited more efficiently [135,184][34][49] (Table 21).

11. The Mechanisms of lncRNA Regulation by Phytochemicals

In recent years, several lncRNAs with interfering properties have been identified in different types of cancers. Thus far, the exact mechanism of lncRNA regulation in normal physiology or cancer cells is still unknown [185,186][119][120]. There is some evidence suggesting that lncRNAs are involved in the regulation of gene expression via transcriptional and post-transcriptional mechanisms and chromatin modification [9][121]. Furthermore, previous studies have defined that phytochemicals change the dysregulation of lncRNAs in various cancer types [187,188][122][123].

12. Transcriptional and Post-Transcriptional Regulation of lncRNAs

TOP2A is a necessary element for the transcriptional activity of RNA polymerase II, which leads to a reduction of LS Pol II-mediated H19 transcription. Kujundzic and coworkers demonstrated that curcumin downregulates TOP2A expression and consequently inhibits H19 expression in tumor cell lines [191][124]. In another study, it was shown that curcumin regulates H19 through affecting the PI3K/Akt signaling pathway [192,193,194][125][126][127]. It was also shown that 3,3′-diindolylmethane inhibited the expression of PCGEM1 by banning its interaction with a nuclear RNA-binding protein, p54/nrb [103][71]. EGCG suppresses the promoter of the Cu(I) transport gene 1 (CTR1) in cancer cells, while it induces it through NEAT1, which is associated with hsa-miR-98-5p [195,196,197,198][128][129][130][131]. Furthermore, HOTAIR upregulates c-Myc in breast and ovarian cancers, which in turn promotes cancer cell proliferation [7][132]. Genistein downregulates the expression of HOTAIR at the transcription level in several cancers. The AR activation is a significant element in castration-resistant prostate cancer (CRPC) and increasing the expression level of HOTAIR [199][133].

13. Chromatin Modification by lncRNAs

lncRNAs are vital regulators of the genome structure, are able to interact with chromatin-modifying enzymes, and control the chromatin structure and accessibility to genetic information through reprogramming mechanisms [200,201][134][135]. The DNA methylation of genes inhibits the regulation of histone-modifying enzymes, which contributes to prostate cancer progression [175][103]. Several lncRNAs, such as PTENP1, Linc00963, PCGIM1, PRNCR1, CBR-3AS1, CTP1AS, GAS5, ANRIL, ANRASSF1, and PCAT1, upregulate the proliferation of cancer cells [59,74,102,175,202,203,204,205,206,207,208,209,210][22][136][137][103][138][139][140][141][142][143][144][145][146]. Resveratrol blocked the reduction of PCAT29 expression of this lncRNA in hepatocellular carcinoma [98][147]. HOTAIR can act as a mediator of proliferation, migration, invasion, and apoptosis in breast, liver, and colon cancer metastasis through genetic regulation [62,86,211][62][58][148]. Generally, lncRNAs are impartible vital molecules that are involved in gene modification and reprogramming. Phytochemicals, with their regulatory effects on lncRNAs, can be helpful as natural drugs for various cancer therapies.

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