TXNDC9 promotes hepatocellular carcinoma progression by positive regulation of MYC-mediated transcriptional network

Dawei Chen; Jixue Zou; Zhenguo Zhao; Xiaodong Tang; Zhicheng Deng; Jingchao Jia; Shuanghai Liu

doi:10.1038/s41419-018-1150-4

TXNDC9 promotes hepatocellular carcinoma progression by positive regulation of MYC-mediated transcriptional network

Cell Death Dis. 2018 Oct 31;9(11):1110. doi: 10.1038/s41419-018-1150-4.

Authors

Dawei Chen¹, Jixue Zou², Zhenguo Zhao¹, Xiaodong Tang¹, Zhicheng Deng¹, Jingchao Jia¹, Shuanghai Liu³

Affiliations

¹ Department of Hepatopancreatobiliary Surgery, Jiangyin People's Hospital, School of Medicine, Southeast University, No. 163, Shoushan Road, Jiangyin, 214400, Jiangsu Province, China.
² Liver Cancer Institute, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai, 200032, China.
³ Department of Hepatopancreatobiliary Surgery, Jiangyin People's Hospital, School of Medicine, Southeast University, No. 163, Shoushan Road, Jiangyin, 214400, Jiangsu Province, China. shuanghaimed@yeah.net.

Abstract

The thioredoxin domain containing proteins are a group of proteins involved in redox regulation and have been recently reported to be associated with tumor progression. However, the role of thioredoxin proteins in hepatocellular carcinoma (HCC) remains largely unknown. Here in our study, we demonstrated that thioredoxin domain containing protein 9 (TXNDC9) was over-expressed in HCC and promoted HCC progression. We found that TXNDC9 expression was amplified in HCC tissues and associated with an advanced grade of HCC. And, we demonstrated that overexpression of TXNDC9 was correlated with poor prognosis of HCC. Furthermore, by using CRISPR-Cas9 mediated TXNDC9 knockout and RNA-seq analysis, we found that TXNDC9 accelerated HCC proliferation regulation. Moreover, we demonstrated that TXNDC9 directly interacted with MYC and knockout/knockdown of TXNDC9 decreased the protein levels of MYC and inhibited MYC-mediated transcriptional activation of its targets. Besides, we identified that TXNDC9 was trans-activated by FOXA1, JUND, and FOSL2 in HCC. Taken together, our study unveiled an oncogenic role of TXNDC9 in HCC and provided a mechanistic insight into the TXNDC9 mediated gene regulation network during HCC development.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Carcinoma, Hepatocellular / genetics*
Carcinoma, Hepatocellular / mortality
Carcinoma, Hepatocellular / pathology
Carcinoma, Hepatocellular / surgery
Cell Line, Tumor
Cell Movement
Cell Proliferation
Disease Progression
Female
Fos-Related Antigen-2 / genetics
Fos-Related Antigen-2 / metabolism
Gene Expression Profiling
Gene Expression Regulation, Neoplastic*
Gene Ontology
Hepatocyte Nuclear Factor 3-alpha / genetics
Hepatocyte Nuclear Factor 3-alpha / metabolism
Humans
Liver Neoplasms / genetics*
Liver Neoplasms / mortality
Liver Neoplasms / pathology
Liver Neoplasms / surgery
Male
Middle Aged
Molecular Sequence Annotation
Neoplasm Staging
Proto-Oncogene Proteins c-jun / genetics
Proto-Oncogene Proteins c-jun / metabolism
Proto-Oncogene Proteins c-myc / genetics*
Proto-Oncogene Proteins c-myc / metabolism
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Signal Transduction
Survival Analysis
Thioredoxins / genetics
Thioredoxins / physiology*
Transcription, Genetic

Substances

FOSL2 protein, human
FOXA1 protein, human
Fos-Related Antigen-2
Hepatocyte Nuclear Factor 3-alpha
JunD protein, human
MYC protein, human
Proto-Oncogene Proteins c-jun
Proto-Oncogene Proteins c-myc
RNA, Small Interfering
TXNDC9 protein, human
Thioredoxins