The novel miR-1269b-regulated protein SVEP1 induces hepatocellular carcinoma proliferation and metastasis likely through the PI3K/Akt pathway

Lu Chen,Bo Sun,Lisha Qi,Dongming Liu,Hua Guo,Qiang Li,Xiangdong Tian,Xianfu Yi,Qiuping Dong,Ti Zhang,Wei Zhang,Tianqiang Song,Mingxi Guo,Zhiqiang Han

doi:10.1038/s41419-020-2535-8

Abstract

Decreased intercellular adhesion is a key step in the metastasis and recurrence of many cancers, including hepatocellular carcinoma (HCC). SVEP1 is an important cell adhesion molecule that plays a key role in regulating intercellular adhesion and embryonic lymphatic development. However, the expression patterns and roles of SVEP1 in HCC are still largely unknown. We identified SVEP1 expression by analyzing 220 HCC samples from our cancer center. TCGA and GEO online-databases were used for data calibration and validation. SVEP1 was differentially expressed in two groups of HCCs with different risks of recurrence and was deemed as an independent risk factor for the prognosis of HCC. The expression of SVEP1 is negatively related to the proliferation and metastasis of HCC. Downregulation of SVEP1 expression promoted in vitro HCC cell migration, chemotaxis, invasion and proliferation, as well as in vivo tumor growth, local invasion and metastasis in a mouse model. Bioinformatic analysis and RT-PCR results showed that miR-1269b expression is negatively correlated with the SVEP1 expression and the prognosis of HCC patients. Further experiments showed that miR-1269b directly targets and downregulates the expression of SVEP1, which further induces the phosphorylation of Akt at thr308. These regulatory effects ultimately mediate the proliferation and metastasis of HCC cells. SVEP1 could serve as a promising prognostic marker of HCC. MiR-1269b downregulates SVEP1 expression and promotes HCC proliferation and metastasis likely through the PI3k/Akt signaling pathway.

Highlights

Primary liver cancer (PLC) is the second leading cause of cancer-related death worldwide
We found that DPT17, PKP318 and ITGB819 were all known to be correlated with tumor progression and metastasis
We further investigated the differential prognosis between high-SVEP1 expression Hepatocellular carcinoma (HCC) and low-SVEP1 expression level HCCs in two high-risk relapse subgroups: tumor diameter ≥3 cm and tumor with satellite nodules. In these two subgroups, there was no significant difference in overall survival (OS) (p = 0.246, p = 0.105, Fig. 2h and i); patients with high levels of SVEP1 expression still had a longer disease-free survival (DFS) time than patients with low-SVEP1 expression levels (p = 0.041, p = 0.021, Fig. 2j and k). These results suggest that a low level of SVEP1 expression is a critical feature of HCC that might pave the way for tumor proliferation and metastasis

Summary

Introduction

Primary liver cancer (PLC) is the second leading cause of cancer-related death worldwide. Surgical resection and liver transplantation are considered to be the best approaches for early-stage HCC treatment[3]. When it comes to intermediate stage-Barcelona Clinic Liver Cancer (BCLC) B stage HCC, it is difficult to determine which treatment is more appropriate. Some patients achieve better survival after surgical resection, while others experience recurrence and metastasis within a short period of time after surgery[4,5]. Short-term recurrence and metastasis after surgery is one of the main factors affecting the prognosis of patients with HCC, especially BCLC B stage patients[6]

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Results

Conclusion