TMED3 promotes hepatocellular carcinoma progression via IL-11/STAT3 signaling.

Hao Zheng,Li-Jun Ma,Tao Tian,Yuan Yang,Wei-Hua Jiang,Cheng Chen,Meng-Chao Wang,Jun Han,Wei-Ping Zhou,Rong Gao,Shuai Li,Jian Wang,Hao Ren

doi:10.1038/srep37070

Abstract

Transmembrane p24 trafficking protein 3(TMED3) is a metastatic suppressor in colon cancer, but its function in the progression of hepatocellular carcinoma (HCC) is unknown. Here, we report that TMED3 was up-regulated in HCC and portal vein tumor thrombus. TMED3 up-regulation in HCC was significantly correlated with aggressive characteristics and predicted poor prognosis in HCC patients. TMED3 overexpression in HCC cell lines promoted cell migration and invasion. In contrast, TMED3 knockdown suppressed HCC metastasis both in vitro and in vivo. Gene microarray analysis revealed decreased IL-11 expression in TMED3-knockdown cells. We propose that TMED3 promotes HCC metastasis through IL-11/STAT3 signaling. Taken together, these findings demonstrate that TMED3 promotes HCC metastasis and is a potential prognostic biomarker in HCC.

Highlights

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies[1,2,3]
Expression levels in 60 cases of hepatocellular carcinoma (HCC), including 25 MI and 35 NMI, were analyzed by RT-PCR and normalized to β-actin. (B) Relative TMED3 mRNA expression levels in 30 cases of HCC with portal vein tumor thrombus (PVTT) were analyzed by RTPCR and normalized to β-actin. (C) The high TMED3 expression group had a shorter relapse-free survival (RFS) than the low TMED3 expression group. (D) The high TMED3 expression group had a shorter overall survival (OS) than the low TMED3 expression group. *p < 0.05, **p < 0.01, ***p < 0.001
To further investigate the role of TMED3 in HCC metastasis, we examined TMED3 expression in primary metastatic or non-metastatic HCC

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies[1,2,3]. With improvements in surgical techniques and perioperative management, the five-year survival rates for HCC after curative therapy have somewhat increased[2,4,5]. TMED proteins primarily exist as monomers, dimers, oligomers and hetero-oligomers in eukaryotes[12,13,14]. These proteins contain a GOLD (Golgi dynamics) domain, which is a β-strand-rich domain found in several proteins that are involved in Golgi dynamics and intracellular protein trafficking[13,15]. A gene microarray analysis of a TMED3-knockdown cell line revealed low IL-11 expression. These findings suggest that TMED3 plays an important role in HCC progression through IL-11/STAT3 signaling and may be useful for future HCC therapy. Expression levels in 60 cases of HCC, including 25 MI and 35 NMI, were analyzed by RT-PCR and normalized to β-actin. (B) Relative TMED3 mRNA expression levels in 30 cases of HCC with PVTT were analyzed by RTPCR and normalized to β-actin. (C) The high TMED3 expression group had a shorter RFS than the low TMED3 expression group. (D) The high TMED3 expression group had a shorter OS than the low TMED3 expression group. *p < 0.05, **p < 0.01, ***p < 0.001

Methods

Results

Conclusion