MTBP Promotes the Invasion and Metastasis of Hepatocellular Carcinoma by Enhancing the MDM2-Mediated Degradation of E-Cadherin.
BACKGROUND
Emerging evidence suggests that MTBP plays a role in cancer development and possibly progression, but its influence on hepatocellular carcinoma (HCC) remains unclear.


METHODS
We used real-time PCR and Western blotting to investigate MTBP expression in four HCC cell lines, 120 pairs of tumor and corresponding paracarcinomatous tissues from HCC patients. Immunohistochemistry was performed to examine MTBP expression in HCC and corresponding paracarcinomatous tissues from 120 patients. E-cadherin was only examined in HCC tissues of patients mentioned above. Statistical analyses were applied to evaluate the prognostic value and associations of MTBP expression with clinical parameters. Furthermore, the MTBP gene was overexpressed in HepG2 cell and silenced by siRNA in Hu7 cell, and cell migration and invasion were detected in vitro and in vivo. Moreover, the molecular mechanism of E-cadherin regulation by MTBP was explored.


RESULTS
In this study, we first showed that MTBP protein expression is positively correlated with distant metastasis and poor prognosis in HCC patients. We also found that MTBP expression was increased in metastatic cell lines when compared with nonmetastatic cell lines. Consistent with these findings, enhanced expression of MTBP promoted HCC cell invasiveness and metastasis both in vitro and in vivo, whereas the knockdown of MTBP with small interfering RNA resulted in reduced HCC migration and invasion. Ectopic expression of MTBP in HCC cells induced epithelial-to-mesenchymal transition, whereas the silencing of MTBP had the opposite effect. Furthermore, our results show that MTBP and E-cadherin protein expression are inversely correlated in primary HCC tissues. Moreover, our findings indicate that MTBP overexpression decreases E-cadherin expression through the modulation of Mdm2 ubiquitination degradation.


CONCLUSIONS
Our data show that MTBP aggravates the invasion and metastasis of HCC by promoting the MDM2-mediated degradation of E-cadherin.
Department of Gastroenterology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China. shanlua2341@126.com.|Department of Oncology, Jiangxi Provincial Cancer Hospital, Nanchang, 330029, China. shanlua2341@126.com.|Jiangxi Province Key Laboratory of Molecular Medicine, Nanchang, 330006, China. shanlua2341@126.com.
Shan
S
Lu
Department of Gastrointestinal Surgery, Jiangxi Provincial Cancer Hospital, Nanchang, 330029, China.
Wei
W
Zhou
Department of Gastrointestinal Surgery, Jiangxi Provincial Cancer Hospital, Nanchang, 330029, China.
Haiyun
H
Wei
Jiangxi Province Key Laboratory of Molecular Medicine, Nanchang, 330006, China.
Leifeng
L
He
Jiangxi Province Key Laboratory of Molecular Medicine, Nanchang, 330006, China.
Liang
L
Li
D015820:Cadherins / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D009362:Neoplasm Metastasis / Q000503:physiopathology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D012313:RNA / Q000235:genetics / Q000378:metabolism
D015820:Cadherins; D002352:Carrier Proteins; C485931:MTBP protein, human; D012313:RNA; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
E-cadherin; Hepatocellular carcinoma; Invasion; MTBP; Ubiquitination