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  • br Ethics statements br Introduction Hepatocellular carcinom


    Ethics statements
    Introduction Hepatocellular carcinoma (HCC) is the fifth most common malignant tumor and the third leading cause of cancer-related mortality worldwide, with rapidly-increasing incidence in recent years [1,2]. Mounting evidence shows that viral hepatitis, toxin exposure, non-alcoholic fatty liver disease and excessive alcohol abuse are the primary risk factors of HCC [3]. Despite great improvements have been made in early diagnosis and therapeutic strategies for HCC in the past few decades, the prognosis for HCC patients remains dismal, with the overall five-year survival rate of approximately 30% for advanced HCC patients [4,5]. It is believed that high recurrence and tumor metastasis potential lowers the long-term survival of HCC patients [6]. The delayed diagnosis and lack of effective treatment for advanced HCC gives rise to the unsatisfactory prognosis of HCC patients. Therefore, it is imperative to seek for the specific mechanisms underlying HCC pathogenesis, which contributes to identify new biomarkers and develop new therapeutic strategies for HCC. LncRNAs, a class of ncRNAs with more than 200 nucleotides in length and limited protein-coding potential, have recently received great attention due to their functional roles in a variety of biological processes and diseases [7]. LncRNAs have been highlighted to be implicated in the regulation of gene expressions via interactions with different molecules in tumorigenesis [8], offering the possibility of lncRNAs as novel biomarkers for cancer diagnosis, therapy and prognosis [9]. Moreover, plenty of lncRNAs have been identified as oncogenic drivers or tumor suppressors in HCC by modulation of cell proliferation, apoptosis, autophagy, invasion and metastasis via various pathways [10,11]. For instance, knockdown of lncRNA GHET1 blocked cell proliferation, induced NAD+ arrest and cell apoptosis in HCC through repressing transcription of KLF2 by recruiting PRC2 onto KLF2 promoter region [12]. Increased NNT-AS1 expression promoted cell proliferation and cell cycle progression, and decreased cell apoptosis via regulating miR-363/CDK6 pathway in HCC [13]. DBH-AS1, a ∼2 kb lncRNA with a polyadenylated tail, is transcribed from chromosome 9q34 [14]. DBH-AS1 was reported to be highly expressed in HCC tissues and cells, and DBH-AS1 overexpression significantly promoted cell proliferation and survival through activation of MAPK signaling in HCC [15]. As highly conserved small ncRNAs with 19–25 nucleotides in length, microRNAs (miRNAs) are well-documented to negatively regulate gene expression post-transcriptionally through combining with the specific sequences in the 3’-untranslated region (3’-UTR) of target messenger RNAs (mRNAs) [16]. Dysregulation of mRNAs has been discovered in many human malignancies, including HCC [17]. miR-138, generating from two primary transcripts pri-miR-138-1 and pri-miR-138-2, has been found to exert tumor-suppressive roles by targeting many target genes associated with proliferation, apoptosis, invasion, and migration in many cancer types [17]. Moreover, the anti-tumor properties of miR-138 in HCC have NAD+ been elucidated in lots of documents [[18], [19], [20]]. In recent years, it is proposed that lncRNAs exert “sponge-like” effects on diverse miRNAs, subsequently affecting miRNA-mediated functions [21]. Due to the inverse expression and function of DBH-AS1 and miR-138 in HCC, we further explored whether DBH-AS1 could serve as a molecular sponge of miR-138 to affect HCC development.
    Materials and methods
    Discussion Emerging evidence has highlighted the biological roles and molecular mechanisms of lncRNAs in tumorigenesis of various malignancies including HCC [27]. TCGA database analysis showed that DBH-AS1 was differentially expressed in various cancers. However, little is known about the exact molecular basis of DBH-AS1 in the pathogenesis of HCC. In the present study, we proved that DBH-AS1 expression was notably upregulated in HCC tissues and cell lines, which was in line with a prior report [15]. However, a study pointed out that DBH-AS1 were differentially expressed in HBV-, HCV-, and HDV-related HCC tissues with reduced expression in HBV-related HCC samples [28]. In the present study, we further demonstrated that DBH-AS1 expression was associated with tumor size and advanced pathophysiologic status in HCC. Functional investigations revealed that DBH-AS1 silencing suppressed proliferation and induced apoptosis in HCC cells, which was in accordance with earlier study [15]. Moreover, we further demonstrated that DBH-AS1 overexpression promoted HCC xenograft tumor growth in vivo. Additionally, DBH-AS1 promoted the tumorigenesis of HCC partially by regulating miR-138/FAK/Src/ERK pathway. Previous report pointed out that enforced expression of DBH-AS1 promoted cell cycle progression and the expressions of CDK6, CCND1, and CCNE1, but inhibited the expressions of p16, p21 and p27 [15]. Also, they further demonstrated that DBH-AS1 could be induced by HBx and inactivated by p53, and consequently facilitated cell proliferation and suppressed cell apoptosis by activating MAPK signaling in HCC [15].