title: The miR-545/374a cluster encoded in the Ftx lncRNA is overexpressed in HBV-related hepatocellular carcinoma and promotes tumorigenesis and tumor progression.
abstract: Hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). Previous studies have shown several long noncoding RNAs (lncRNAs) play various roles in HCC progression, but no research has focused on the expression pattern of microRNA clusters encoded in lncRNAs. The Ftx gene encodes a lncRNA which harbors 2 clusters of microRNAs in its introns, the miR-374b/421 cluster and the miR-545/374a cluster. To date, no research has focused on the role of the miR-545/374a and miR-374b/421 clusters in HBV-related HCC. In this study, 66 pairs of HBV-related HCC tissue and matched non-cancerous liver tissue specimens were analyzed for the expression of the Ftx microRNA clusters. Our results showed that the miR-545/374a cluster was upregulated in HBV-HCC tissue and significantly correlated with prognosis-related clinical features, including histological grade, metastasis and tumor capsule. Transfection studies with microRNA mimics and inhibitors revealed that miR-545/374a expression promoted in vitro cell proliferation, cell migration and invasion. The wild-type HBV-genome-containing plasmid or full-length HBx protein encoding plasmid was transfected into the Bel-7402 cell line and observed for their influence on miR-545/374a expression. We found that transfection of the HBV genome or HBx alone resulted in an increase in miR-545/374a expression. Next, by monitoring the expression of sera miR-545/374a before and after surgical tumor excision, we found serum miR-545/374a was tumor-derived and exhibited a sharp decrease 25 days after tumor excision. We also examined the gender-based difference in miR-545/374a expression among HCC patients and utilized microRNA target prediction software to find the targets of miR-545/374a. One of these targets, namely estrogen-related receptor gamma (ESRRG) was inversely correlated with miR-545 expression. In conclusion, the overexpression of miR-545/374a cluster located in the Ftx lncRNA is partially responsible for a poor prognosis, and monitoring sera levels of miR-545/374a may be a useful diagnostic marker for HCC.
authors.affiliation: Department of Gastroenterology, Provincial Hospital Affiliated to Shandong University, Jinan, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Infectious Diseases, Provincial Hospital Affiliated to Shandong University, Jinan, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: Central Laboratory, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China.
authors.forename: Jianni
authors.initials: J
authors.lastname: Qi
authors.affiliation: Department of Gastroenterology, Provincial Hospital Affiliated to Shandong University, Jinan, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, Provincial Hospital Affiliated to Shandong University, Jinan, China.
authors.forename: Chengyong
authors.initials: C
authors.lastname: Qin
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000235:genetics* / Q000601:surgery / Q000821:virology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006509:Hepatitis B / Q000150:complications / Q000235:genetics* / Q000601:surgery / Q000821:virology; D006515:Hepatitis B virus / Q000235:genetics* / Q000472:pathogenicity; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics* / Q000601:surgery / Q000821:virology; D008297:Male; D035683:MicroRNAs / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D011379:Prognosis; D062085:RNA, Long Noncoding / Q000097:blood / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D054334:Viral Regulatory and Accessory Proteins
chemical_list: C490917:ESRRG protein, human; C000594767:MIR545 microRNA, human; C587995:MIRN374 microRNA 374, human; C547665:MIRN421 microRNA, human; D035683:MicroRNAs; D062085:RNA, Long Noncoding; D011960:Receptors, Estrogen; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein