SOCS6 通过诱导细胞凋亡和抑制血管生成在人前列腺癌中发挥肿瘤抑制作用。

SOCS6 Functions as a Tumor Suppressor by Inducing Apoptosis and Inhibiting Angiogenesis in Human Prostate Cancer.

机构信息

Medical College of Guizhou University, Guizhou, 550025, China.

Department of Urology, Guizhou Provincial People`s Hospital, The Affiliated Hospital of Guizhuo Medical University, Guizhou, 550002, China.

出版信息

Curr Cancer Drug Targets. 2018;18(9):894-904. doi: 10.2174/1568009618666180102101442.

DOI:10.2174/1568009618666180102101442

PMID:29295692

Abstract

BACKGROUND

Our previous studies revealed that the downregulation of Suppressor of cytokine signaling 6 (SOCS6) was correlated with malignant progression of human prostate cancer (PCa).

AIMS

In the current study, we aimed to investigate the tumor suppressive roles of SOCS6 and the underlying mechanisms in PCa.

METHODS

SOCS6 expression in PCa and non-cancerous prostate tissues was compared by immunohistochemistry. Statistical associations of SOCS6 expression with various clinicopathological features and patients prognosis were evaluated. In addition, we investigated SOCS6's functions by overexpressing it in vitro (cell apoptosis, migration and invasion assays) and in vivo (tumor formation, angiogenesis and apoptosis). Moreover, SOCS6-regulated genes were identified by nextgeneration RNA-sequencing analysis, followed by pathway enrichment analysis and in vitro experimental validation.

RESULTS

SOCS6 downregulation was significantly associated with advanced clinical stage (P=0.029) and positive lymph node metastasis (P=0.013) in PCa patients. We also identified SOCS6 as an independent prognostic factor for disease-free survival in PCa patients (P=0.045). Moreover, overexpression of SOCS6 inhibited PCa cell invasion, migration, tumor xenografts growth and angiogenesis, but induced PCa cell apoptosis (P values <0.05). Mechanically, we revealed that SOCS6 expression may induce cell apoptosis coincident with down-regulation of Bcl2 and Hspa1a, and may suppress tumor angiogenesis with downregulation of F7, Fak3 and Frzb.

CONCLUSION

These findings suggest that the reduced expression of SOCS6 may be predictive of unfavorable prognosis in PCa. Thus, SOCS6 may serve as a tumor suppressor and a novel therapeutic target for this cancer.

摘要

背景

我们之前的研究表明，细胞因子信号转导抑制因子 6（SOCS6）的下调与人类前列腺癌（PCa）的恶性进展相关。

目的

本研究旨在探讨 SOCS6 在 PCa 中的肿瘤抑制作用及其潜在机制。

方法

通过免疫组织化学比较 PCa 和非癌前列腺组织中的 SOCS6 表达。评估 SOCS6 表达与各种临床病理特征和患者预后的统计学关联。此外，我们通过体外（细胞凋亡、迁移和侵袭试验）和体内（肿瘤形成、血管生成和凋亡）过表达 SOCS6 来研究 SOCS6 的功能。此外，通过下一代 RNA 测序分析鉴定 SOCS6 调节的基因，然后进行通路富集分析和体外实验验证。

结果

SOCS6 的下调与 PCa 患者的晚期临床分期（P=0.029）和阳性淋巴结转移（P=0.013）显著相关。我们还确定 SOCS6 是 PCa 患者无病生存的独立预后因素（P=0.045）。此外，SOCS6 的过表达抑制了 PCa 细胞的侵袭、迁移、肿瘤异种移植生长和血管生成，但诱导了 PCa 细胞凋亡（P 值均<0.05）。机制上，我们揭示了 SOCS6 的表达可能通过下调 Bcl2 和 Hspa1a 诱导细胞凋亡，并且可能通过下调 F7、Fak3 和 Frzb 抑制肿瘤血管生成。