title: ZKSCAN1 gene and its related circular RNA (circZKSCAN1) both inhibit hepatocellular carcinoma cell growth, migration, and invasion but through different signaling pathways.
abstract: There is increasing evidence that circular RNA (circRNA) are involved in cancer development, but the regulation and function of human circRNA remain largely unknown. In this study, we demonstrated that ZKSCAN1, a zinc finger family gene, is expressed in both linear and circular (circZKSCAN1) forms of RNA in human hepatocellular carcinoma (HCC) tissues and cell lines. Here, we analyzed a cohort of 102 patients and found that expression of both ZKSCAN1mRNA and circZKSCAN1 was significantly lower (P < 0.05) in the HCC samples compared with that in matched adjacent nontumorous tissues by reverse transcription PCR (RT-PCR). The low expression level of ZKSCAN1 was only associated with tumor size (P = 0.032), while the cirZKSCAN1 levels varied in patients with different tumor numbers (P < 0.01), cirrhosis (P = 0.031), vascular invasion (P = 0.002), or microscopic vascular invasion (P = 0.002), as well as with the tumor grade (P < 0.001). Silencing both ZKSCAN1mRNA and circZKSCAN1 promoted cell proliferation, migration, and invasion. In contrast, overexpression of both forms of RNA repressed HCC progression in vivo and in vitro. Silencing or overexpression of both forms of RNA did not interfere with each other. RNA-seq revealed a very different molecular basis for the observed effects; ZKSCAN1mRNA mainly regulated cellular metabolism, while circZKSCAN1 mediated several cancer-related signaling pathways, suggesting a nonredundant role for ZKSCAN1mRNA and circRNA. In conclusion, our results revealed two post-translational products (ZKSCAN1mRNA and circZKSCAN1) that cooperated closely with one another to inhibit growth, migration, and invasion of HCC. cirZKSCAN1 might be a useful marker for the diagnosis of HCC.
authors.affiliation: Department of General Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Yao
authors.affiliation: R&D Unit 602, Forevergen Biosciences Center, Guangzhou, Guangdong, China.
authors.forename: Jingyan
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of General Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Kunpeng
authors.initials: K
authors.lastname: Hu
authors.affiliation: Department of General Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Jizong
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of General Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of General Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Qiangliang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of General Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Xiong
authors.affiliation: R&D Unit 602, Forevergen Biosciences Center, Guangzhou, Guangdong, China.
authors.forename: Chonghua
authors.initials: C
authors.lastname: He
authors.affiliation: Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Zejian
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of General Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Liver Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000818:Animals; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D003710:Demography; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D012313:RNA / Q000235:genetics* / Q000378:metabolism; D000079962:RNA, Circular; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012372:ROC Curve; D015203:Reproducibility of Results; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000079962:RNA, Circular; D012333:RNA, Messenger; D014157:Transcription Factors; D012313:RNA
keywords: 
  HCC
  ; RNA-seq; ZKSCAN1; circular RNA; qRT-PCR