SH3-domain binding protein 1 in the tumor microenvironment promotes hepatocellular carcinoma metastasis through WAVE2 pathway.

Yiming Tao,Zhiming Wang,Kuan Hu,Ming Zhou,Sai Zhang,Fengbo Tan,Jia Luo

doi:10.18632/oncotarget.7786

Yiming Tao, Zhiming Wang + Show 5 more

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https://doi.org/10.18632/oncotarget.7786

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Abstract

SH3-domain binding protein-1 (SH3BP1) specifically inactivating Rac1 and its target WAVE2 is required for cell motility. The present study shows SH3BP1 expression patterns in human HCC tissues and cell lines were examined. The regulation of SH3BP1 on HCC cell migration and invasion related to Rac1-WAVE2 signaling was characterized using in vitro and in vivo models. SH3BP1 overexpressed in HCC tissues and highly metastatic HCC cells was significantly associated vascular invasion (VI). SH3BP1 promoted VEGF secretion via Rac1-WAVE2 signaling, so as to exert an augmentation on cell invasion and microvessel formation. In three study cohorts with a total of 516 HCC patients, high SH3BP1 expression combined with high microvessel density (MVD) was confirmed as a powerful independent predictor of HCC prognosis in both training cohorts and validation cohort. Being an important angiogenic factor of HCC through Rac1-WAVE2 signaling, SH3BP1 promotes tumor invasion and microvessel formation contributing to HCC metastasis and recurrence. SH3BP1 is a novel WAVE2 regulator, a prognostic marker and a potential therapeutic target of HCC.

Highlights

Hepatocellular carcinoma (HCC) is the sixth most common primary liver cancer and the third greatest cause of death from cancer worldwide [1, 2]
Elevated SH3-domain binding protein-1 (SH3BP1) expression levels was associated with HCC metastases quantitative real-time PCR (qRT-PCR) analysis indicated that SH3BP1 messenger RNA (mRNA) was readily detectable in all HCC and paired ANLT tissues of 78 clinical cases
HCC tissues with vascular invasion (HCC-VI) expressed significantly higher levels of SH3BP1 mRNA than HCC tissues without VI (Figure 1a3, 0.0792±0.0059 vs. 0.0368 ± 0.0073, P < 0.01)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the sixth most common primary liver cancer and the third greatest cause of death from cancer worldwide [1, 2]. Continued searching for molecular markers, which is helpful to predict and inhibit recurrence and metastasis, is of great importance in HCC therapy. The recurrence and metastasis of HCC is a multistep process that often involves many complex biological and pathological events [5, 6]. Rac was reported to stimulate lamellipodium formation and contribute to cancer cell invasion by regulating activation of WAVE2 signaling complex [8,9,10]. We previously demonstrated that WAVE2 expression was significantly correlated to vein invasion in HCC [11]. Rac-WAVE2 was reported to be essential for invasion and metastasis of murine melanoma [12]. The molecular mechanisms of Rac1-WAVE2-regulated invasion in HCC needed to be further elucidated. Rac increase VEGF and promoted HCC angiogenesis via direct interaction with HIF-1α to gain an increased HIF-1α stability [14, 15]

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