MicroRNA-638 induces apoptosis and autophagy in human liver cancer cells by targeting enhancer of zeste homolog 2 (EZH2)
Introduction
Liver cancer is one of the devastating human cancers and ranked as the 5th most prevalent type of cancer across the globe (Akinyemiju et al., 2017). Causing significant number of deaths, it is ranked 3rd in terms of mortality and morbidity (Asrani et al., 2019). The liver cancer treatments include partial hepatectomy, liver transplantation together with procedures like ablation or embolization. Chemo/immune- and/or radio-therapies are used against the advanced stage disease (Anwanwan et al., 2020). However, the clinical outcomes of these treatments are far from descent which necessitate the unraveling of the molecular events, controlling the development and progression of liver cancer for the development of efficient treatment strategies. Of the various molecular factors which have been shown to regulate the onset and subsequent progression of of human cancers, the microRNAs (miRs) have emerged as pivotal players in controlling the tumor growth and proliferation (Sun et al., 2014). The miRs are relatively small group of regulatory RNAs which play key regulatory roles in various biological processes in human body (Zhang, 2008). The miRs affect the vital physiological processes like proliferation of eukaryotic cells, cell differentiation and apoptotic cell death pathways (Hwang and Mendell, 2006). As per the recent research findings, the dysregulation of miRs is has been linked with the development of several cancer and thus are considered as crucial biomarkers for cancer prognosis (Hata and Kashima, 2016). They have also been shown exhibit therapuetic applications in controlling the progression and angiogenesis of many cancers (Costouros et al., 2002). Several studies have revealed the regulatory role of different miRs in liver cancer progression and metastasis (Greene et al., 2013). The miR-638 has been previously shown to exert profound regulatory roles in human cancers like colorectal cancer and gastric cancer (Zhang et al., 2014; Zhao et al., 2014). Studies have also shown miR-638 downregulation in liver cancer (Shi et al., 2018). The miR-638 has been shown to regulate the cell invasion and epithelial-to-mesenchymal transition of liver cancer through post-transcriptional targeting of SOX2 (Zhang et al., 2017). Furthermore, miR-638/VEGF axis has been shown to control the liver cancer angiogenesis (Cheng et al., 2016). Nonetheless, the role of miR-638 on the growth of human of liver cancer via modulation of zeste homolog 2 (EZH2) expression is still unknown. The present study was therefore designed to investigate the role of miR-638/EZH2 axis in liver cancer growth and to unravel the underlying mechanisms.
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Tissue samples
The liver cancer tissues, and the normal adjacent tissues were collected prior to chemotherapy at first affiliated hospital of Zhengzhou University from the year June 2018 to June 2019. The general characteristics of the patients are presented in Table 1. The human tissue specimens were obtained under the proper ethical guidelines and written consent was taken from the patients before obtaining the specimens. The study was approved by the Institutional ethics under approval number HZU-401HT-19.
miR-638 is downregulated in liver cancer
The expression level of miR-638 was examined in 25 clinical samples of each cancerous and normal surrounding liver tissues using qRT-PCR method. The results showed that miR-638 is significantly (P < 0.05) downregulated in liver tissues (Fig. 1A). Similarly, the miR-638 expression was also deduced in the cancer cell lines (SNU-182, SNU-423, SNU-449 and SNU-387) and in the normal human cell line (THLE-3). All four liver cancer cell lines exhibited markedly lower transcript levels of miR-638 in
Discussion
Human liver cancer causes significant number of human mortalities and morbidities worldwide (Wong et al., 2017). The overall 5-year survival rates of liver cancer are exceptionally low signifying the necessity of formulating more competent anti-cancer stratagems against this fatal malignancy (Lepage et al., 2015). Recent studies have laid tremendous focus on understanding the various molecular mechanisms regulating the proliferation of liver cancer (Aravalli et al., 2008). Among the different
Conclusion
The results of the present study revealed that miR-638 is significantly downregulated in human liver cancer. Overexpression of miR-638 exerts tumor suppressive effects via induction of apoptosis and autophagy. The study also revealed the involvement of EZH2 in the miR-638 exerted tumor suppressive effects. Taken together, the findings point towards the therapeutic potential of miR-638/EZH2 axis in the management of liver cancer.
CRediT authorship contribution statement
Hongyu Zhang: Conceptualization, Methodology, Software, Data curation, Writing - original draft, Writing - review & editing. Hongxia Liang: Data curation, Writing - original draft. Shuhuan Wu: Data curation, Writing - original draft. Yingying Zhang: Data curation, Writing - original draft. Zujiang Yu: Conceptualization, Methodology, Software, Supervision, Writing - review & editing.
Declaration of Competing Interest
The authors declare that there are no conflicts of interest
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