The emerging roles of long non-coding RNA (lncRNA) H19 in gynecologic cancers

Studies have shown that H19 expression levels are higher in ER-positive tumor tissues than in ER-negative ones, and that 17β-estradiol can increase H19 expression in MCF-7 cells, which are ER-positive. Thus, it can be inferred that H19 is an estrogen-inducible gene that plays a critical role in the survival of MCF-7 cancerous cells [62]. The role of H19 in drug resistance is crucial, as it has been shown to inhibit the pro-apoptotic factors BIK and NOXA, resulting in a decreased rate of apoptotic cell death in response to paclitaxel (PTX). H19 achieves this effect through promoter methylation of BIK [63]. Peng et al. demonstrated a significant increase in H19 expression levels in breast cancer stem cells (BCSCs). Furthermore, they found that overexpression of H19 significantly enhanced mammosphere formation ability, migration, and clonogenicity of BC cells [64]. MRP4 and MDR are the pivotal molecules responsible for conferring resistance to H19 in cancer cells. Upon silencing of the H19 lncRNA in doxorubicin-resistant MCF-7 cells, there was a marked improvement in the sensitivity of cancer cells to chemotherapy agents such as paclitaxel and anthracyclines, accompanied by a significant decrease in the expression levels of MRP4 and MDR1 [65]. Resistance to endocrine therapy is a defining characteristic of ER+ BC. Pratima et al. demonstrated that following treatment of endocrine-resistant BC cells with Fulvestrant and Tamoxifen, there was a significant upregulation in the expression levels of the H19. The expression of H19 is regulated by the c-MET and Notch signaling pathways, and inhibition of these pathways was shown to decrease H19 expression, leading to an increase in the sensitivity of endocrine-resistant cells to Fulvestrant and Tamoxifen [67]. A different research revealed that inhibiting the EMT and Wnt signaling pathway through knockdown of H19 not only enhances the rate of apoptosis and sensitivity to tamoxifen but also reduces the invasiveness of cancer cells [68]. Han et al. demonstrated that silencing of H19 enhanced the chemosensitivity of triple-negative breast cancer (TNBC) cell lines to PTX by promoting apoptosis through the regulation of the Akt signaling pathway [69]. Numerous studies have confirmed that aldehyde dehydrogenase 1 (ALDH1) is a well-established marker of stem cells. Shima et al. reported a strong association between ALDH1 positivity and H19 expression in BC patients. They also demonstrated that the silencing of H19 significantly decreased the ability of cancer cells to form spheres, indicating a potential role for H19 in regulating the stemness of BC cells [101]. The involvement of H19 in tamoxifen resistance in BC cell lines has been attributed to its interaction with SAHH, which decreases DNMT3B expression and promotes Beclin1, subsequently enhancing the autophagy process. Knockdown of H19 has been shown to reduce tamoxifen resistance by increasing the methylation of the Beclin1 promoter by DNMT3B [70]. In trastuzumab-resistant BC cells, there is a notable upregulation in the expression levels of H19. However, studies have shown that silencing of H19 can effectively overcome trastuzumab resistance in these cells [71]. H19 has been shown to significantly promote invasion, metastasis, cell proliferation, and EMT process while inhibiting apoptosis in PTX-resistant BC cells. Conversely, silencing of H19 has been demonstrated to have the opposite biological effects, suggesting a potential role for H19 in the development and progression of PTX-resistant BC [73]. The involvement of H19 in doxorubicin resistance has been observed in both tissue and cancerous cell lines. H19 promoted drug resistance by downregulating PARP1, a key regulator of DNA repair, highlighting the potential role of H19 in modulating cellular responses to chemotherapy agents [74]. NFAIP8, a target gene of p53 and a key player in the progression of cancer through various mechanisms such as EMT, is upregulated by H19 through its antagonistic effect on p53. Silencing of either TNFAIP8 or H19 has been shown to reduce the proliferation, invasion, migration, and expression of EMT markers, while increasing the arrest of the cell cycle. These findings suggest that the H19/p53/TNFAIP8 axis plays a critical role in tumor progression mediated by the upregulation of TNFAIP8 through the inhibition of p53 by H19 [75]. Figure 2 illustrates the various mechanisms by which H19 contributes to the progression of BC.

H19 has been found to play a role in the development of ovarian cancer by regulating various pathways, as evidenced by increased expression levels in cisplatin-resistant A2780-DR cells. Further investigations, both in vitro and in vivo, have shown that knockdown of H19 leads to increased sensitivity of A2780-DR cells to cisplatin and reduced expression of NRF2-targeted proteins, including G6PD, GSR, NQO1, GCLM, GSTP1, and GCLC. Given its involvement in the glutathione metabolism pathway, it can be concluded that H19 contributes to drug resistance by modulating glutathione metabolism [83]. Li et al. has demonstrated that H19 plays a crucial role in TGF-β-induced EMT, and that this function is exerted through the sponging of miR-370-3p by the H19 [84]. The anti-seizure drug valproic acid has been shown to decrease the expression of H19 in the cisplatin-resistant ovarian cell line A2780/CP. Subsequent silencing of H19 led to a significant increase in both the rate of apoptosis and sensitivity to cisplatin in the A2780/CP cell line [85]. The modulation of glycolysis metabolism by H19 has been shown to regulate the Warburg effect, as reported by Zheng et al. Specifically, silencing of H19 resulted in decreased glucose consumption, PKM2 expression, and lactate production. This function was found to be exerted through the sponging of miR-324-5p by H19 [86]. In the cisplatin-resistant ovarian cancer cell line OVCAR3/DDP, the expression level of H19 was found to be significantly increased compared to the OVCAR3 cell line. Additionally, OVCAR3/DDP cells exhibited upregulation of EMT markers such as slug, twist, and snail, and decreased E-Cadherin levels. Subsequent knockdown of H19 in OVCAR3/DDP cells led to a suppression of migration and EMT-positive markers, while promoting E-Cadherin expression [87]. Recent reports suggest that Ginsenoside Rg3, a tetracyclic triterpenoid, has the ability to inhibit proliferation, invasion, migration, and colony formation of ovarian cancer cells. Additionally, treatment with Ginsenoside Rg3 was found to decrease the expression of N-cadherin while increasing E-cadherin levels, and these effects were attributed to the suppression of H19 [90]. Figure 3 shows different signaling pathways associated with H19 that impact ovarian cancer.

The expression level of H19 was found to be modulated under conditions of both TGF-β and hypoxia. H19 has the ability to enhance both independent growth and anchorage-specific growth of cervical cancer cell lines [78]. Previous studies have indicated that SIRT1 plays a critical role in various biological processes, including cancer progression. Lei et al. have demonstrated that SIRT1 is a direct target of miR-138-5p in ovarian cancer, and that overexpression of miR-138-5p results in G0/G1 cell cycle arrest, induction of apoptosis, and inhibition of cell proliferation. However, in contrast, H19 has been shown to upregulate SIRT1 and promote cervical cancer progression via sponging of miR-138-5p [80]. Another study has reported that silencing of H19 results in decreased cell proliferation, induction of apoptosis, and cell cycle arrest in the cervical cancer cell lines OV90 and SKOV3 [82]. Figure 3 displays various H19-related signaling pathways that have an impact on cervical cancer.

The role of H19 in the progression of endometriosis has been the subject of conflicting findings in previous studies. While some investigations have reported upregulation of H19 expression in tumoral tissue compared to control, others have reported the opposite results. Sanaz et al. reported that the expression level of H19 in patients with eutopic endometrium was significantly lower than that of normal controls [91]. Another study has shown that H19 plays a role in the progression of endometrial cancer by affecting the EMT process. Silencing of H19 was found to reduce invasion and migration in the HEC-1-B cancer cell line, while also leading to a decrease in Snail expression and an increase in E-cadherin expression. Based on these findings, it can be concluded that H19 promotes endometriosis by modulating the EMT process [93]. It was found that the expression of H19 was significantly suppressed in mononuclear cells obtained from peritoneal fluid of patients with endometriosis [94]. It has been reported that H19 can stimulate the formation of fibrotic tissue in women suffering from endometriosis through the H19/miR-216a-5p/ACTA2 pathway. miR-216a-5p can bind to H19 and to ACTA2 in the 3′ untranslated region (3′UTR) [96]. In vivo investigations using a nude mouse model have demonstrated that silencing of H19 leads to a significant decrease in endometriosis [97]. It has been observed that 17β-estradiol plays a role in regulating the expression pattern and function of H19 in patients with endometriosis. Based on these findings, it can be concluded that 17β-estradiol is involved in the development of endometriosis through the regulation of H19 [98]. According to a study by Sedigheh et al., the expression level of H19 was found to be significantly decreased in both ectopic and eutopic endometrial tissues compared to control tissues. The researchers suggested that H19, through downregulation of IGFI and IGFII, leads to impairment of cellular growth regulation and differentiation [99]. Figure 3 presents different signaling pathways associated with H19 that exert an impact on endometrial cancer.

Several studies have highlighted the role of lncRNAs as ceRNAs that sequester specific miRNAs, thereby diminishing their regulatory impact on target mRNA genes. This interaction between miRNAs and lncRNAs plays a significant role in the development and progression of GCs. Notably, H19 has been identified as a key participant in miRNA sponging within GCs, including miRNA let-7 [64], miR-200b/c [66], miR-491-5p [72], miR-340-3p [73], miR-138-5p [80], miR-370-3p [84], miR-324-5p [86], miR-140 [89], let-7 [91], miR-612 [58], miR-342-3p [94], miR-124-3p [95], and miR-216a-5p [96]. H19 functions as a ceRNA by sequestering let-7, thereby upregulating LIN28 as a direct target of let-7. Conversely, the upregulation of LIN28 suppresses let-7 biogenesis, establishing a reciprocal negative feedback loop involving H19, let-7, and LIN28 as a transcriptional factor [64]. In addition, Wu et al. reported that H19, through its interaction with miR-200b/c and let-7b, modulates the expression of its target genes GIT2 and CYTH3, respectively, which encode regulators of the RAS superfamily. This modulation promotes cell migration and EMT in tumor cells [66]. Also, H19 negatively regulated miR-491-5p expression and inversely modulated ZNF703 expression as a target of miR-491-5p. Therefore H19/miR-491-5p/ZNF703 axis has a critical role in development of BC [72]. Furthermore, H19 has been shown to regulate the expression of miR-491-5p and inversely modulate ZNF703, playing a critical role in breast cancer development [73]. In cervical cancer, H19 acts as a miR-138-5p sponge, reducing SIRT1 expression as a miR-138-5p target gene [80]. Moreover, H19 is involved in the TGF-β/H19/miR-370-3p/EMT signaling axis in ovarian cancer progression [84]. In ovarian cancer, H19 regulates the Warburg effect by directly binding to miR-324-5p and upregulating PKM2, a target of miR-324-5p, thereby enhancing glycolysis metabolism [86]. The H19/miR-140/Wnt1 axis is pivotal in promoting proliferation and migration in ovarian cancer [89]. In endometrial stromal cells, the H19/let-7/IGF1R axis is involved in impaired endometrial proliferation [91]. Furthermore, H19 regulates the percentage of Th17 cells/CD4+ T cells and IL-17 levels via the miR-342-3p/IER3 axis [58]. Elevated H19 levels in ectopic endometrial cells contribute to cell proliferation and invasion through modulation of miR-124-3p and ITGB3 [94]. In women with endometriosis, ectopic endometrial cells have an increasing level of H19. Cell proliferation and invasion was inhibited after H19 down-regulation. H19 exerts this function by modulating miR-124-3p and ITGB3 [95]. Additionally, estrogen-induced alterations in stromal cell invasion and migration in endometriosis are mediated by the H19/miR-216a-5p/ACTA2 axis [96]. Figure 4 provides an overview of the crucial H19-miRNAs involved in the pathogenesis of GCs.

The successful translation of laboratory-based and pre-clinical findings in biology and molecular research to a clinical context plays a pivotal role in advancing cancer research. This critical process necessitates the modification and adaptation of experimental results to render them applicable in clinical settings. Ultimately, the effective translation of basic research findings to clinical practice is imperative for enhancing our comprehension of gynecologic cancers and devising efficacious therapeutic approaches to benefit patients [102]. It was found that the expression levels of H19 were significantly elevated in atypical in situ breast lesions within a Lebanese population, surpassing those in non-malignant lesions. Notably, the highest levels of H19 were detected in malignant tissues. These compelling findings indicate that H19 has the potential to serve as a promising biomarker for the early detection of BC [103]. The clinical significance of H19 levels has been investigated in plasma liquid biopsies, an emerging and dynamic field of research due to its non-invasive and easily accessible nature. Zhang et al., illustrated that the levels of H19 were markedly elevated in the serum of BC patients compared to healthy individuals. Additionally, increased levels of circulating H19 were found to be correlated with hormone receptor expression and lymph node metastasis. The study also determined a specificity of plasma H19 levels for BC exceeding 0.85, emphasizing its potential as a reliable biomarker for BC [59]. It was shown that pre-therapeutic serum levels of H19 could serve as a predictive indicator of neoadjuvant treatment outcomes in BC patients. Notably, patients with lower levels of serum H19 were shown to have a higher probability of achieving a complete pathological response to the treatment. Interestingly, patients with elevated plasma H19 levels were found to exhibit the triple-negative BC subtype. These significant findings suggest that H19 holds promise as a valuable biomarker for predicting treatment response and identifying specific disease subtypes in BC patients [104]. In the context of TNBC, increased levels of H19 have been linked to reduced overall survival and disease-free survival durations. Furthermore, a separate study unveiled an association between the rs2107425 single nucleotide polymorphism (SNP) located near H19 and decreased metastasis-free survival. Moreover, serum levels of H19 have been demonstrated to decline following mastectomy, indicating the potential clinical value of H19 in assessing the efficacy of surgical interventions [32, 105]. Zhang et al. examined the relationship between genetic variations in the IGF2/H19 gene locus and the risk of developing epithelial ovarian cancer (EOC) in a Chinese population. Their findings unveiled a noteworthy connection, indicating that three specific polymorphisms, namely rs3741206, rs2525885, and rs2839698, were significantly associated with an elevated susceptibility to EOC, particularly in patients aged 47 years and older. Moreover, within the rs2525885 subgroup, individuals possessing the TC + CC genotype demonstrated a higher likelihood of advanced FIGO stage, implying that this particular polymorphism may not only contribute to the initiation of cancer but also exert influence on the progression of tumors [88]. Higher levels of H19 expression in tumor tissues among EOC patients were found to be linked with shorter overall survival, indicating its potential as a prognostic marker. Moreover, H19 expression was identified as a predictive factor for carboplatin resistance in EOC cells, suggesting its involvement in the development of chemoresistance and unfavorable treatment outcomes in this disease [106]. The impact of IGF2/H19 gene polymorphisms on platinum resistance has also been investigated in EOC patients. A study by Zeng et al. revealed that individuals with the rs4244809 GG genotype exhibited increased sensitivity to platinum-based chemotherapy agents [107]. Additionally, serum H19 has emerged as a potential biomarker for the diagnosis and monitoring of cervical cancer. Zhao et al. observed elevated levels of serum H19 in cervical cancer patients compared to healthy individuals, with a significant reduction after surgery. Serum H19 exhibited a specificity of nearly 95% in diagnosing cervical cancer, although its sensitivity was relatively low at 30.8%. Notably, plasma H19 levels did not show an association with tumor stage [108]. H19 gene polymorphisms were found to have predictive value for clinicopathological features in cervical cancer patients. In a study involving a Tai population, patients with CC/CT genotypes in H19 rs2839698 demonstrated a lower risk of pelvic node metastasis compared to those with the TT genotype. Similarly, patients with AA/AG genotypes in rs3741219 exhibited a lower risk of pelvic lymph node metastasis, as well as lower rates of parametrium and vaginal invasion, compared to those with the GG genotype. However, no statistically significant differences in prognostic parameters were observed among the various SNP polymorphisms [81]. According to Liu et al., both eutopic and ectopic endometrial tissues in endometriosis patients exhibited upregulated H19 expression, which positively correlated with disease recurrence, infertility, bilateral ovarian lesions, and the revised American Fertility Society (rAFS) stage. Their study demonstrated that high ectopic H19 expression had a sensitivity of 90.9% in predicting disease recurrence [61]. However, in contrast to these findings, Szaflik et al. reported decreased levels of H19 expression in endometrial tissues of endometriosis patients compared to healthy controls. Furthermore, among endometriosis patients, there was an association between H19 expression and the rAFS score for reproductive medicine classification of endometriosis (rASRM) score [100].

Despite the remarkable discoveries regarding the utilization of tissue/serum H19 levels in assessing the clinical characteristics of GC patients, there remains a need for further investigation to establish the expression level or specific single nucleotide polymorphisms (SNPs) of H19 as a suitable biomarker. One limitation is the current scarcity and heterogeneity of the studied SNPs, which necessitates their validation in larger populations. Additionally, certain studies have focused on restricted populations where the expression level of H19 could be influenced by various confounding factors. The role of H19 in endometriosis, as revealed by both clinical and basic studies, presents contradictory data, highlighting the need for additional confirmation. Furthermore, the availability of studies assessing sensitivity and specificity is limited, and they employ diverse sources such as tissue and serum samples. Moreover, some reported ratios exhibit low values and lack potential reliability, thereby making false results unavoidable without further confirmatory research.