Department of Hepatobiliary Surgery of the First Affiliated Hospital& Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116027, China.
Department of Oncology of the First Affiliated Hospital, Dalian Medical University, Dalian, 116027, China.
J Exp Clin Cancer Res. 2018 Jan 31;37(1):17. doi: 10.1186/s13046-018-0691-9.
The tumour microenvironment is essential for cancer progress and metastasis. Integrin-β5 (ITGB5), a member of the integrin family, has been implicated to mediate the interactions of cells with the extracellular matrix (ECM) and promote tumorigenesis in several malignancies. However, the role of ITGB5 in hepatocellular carcinoma (HCC) is still unknown.
The biological function of ITGB5 in HCC was investigated using migration, colony formation assays. The potential molecular mechanism of ITGB5 in regulating HCC tumorigenesis and β-catenin stabilization was investigated by western blotting, co-immunoprecipitation and ubiquitination assays. The expression level of ITGB5 mediated by miR-185 was confirmed by bioinformatic analysis, luciferase assay. The clinical significance of ITGB5 was based on human tissue microarray (TMA) analysis.
Here, we found that the expression of ITGB5 is increased in HCC tissues. Elevated ITGB5 markedly facilitates HCC cell migration and tumorigenesis in vitro and in vivo. Further mechanistic studies revealed that ITGB5, as a partner of β-catenin, directly interacts with β-catenin and inhibits its degradation, thus leading to WNT/β-catenin activity. Subsequently, we also found that ITGB5 is a direct targeted gene of miR-185. The downregulation of miR-185 in HCC cells promotes an increase in ITGB5. An additional increase of ITGB5 is associated with β-catenin upregulation and a miR-185 decrease in HCC tissues.
Our data reveal that the miR-185-ITGB5-β-catenin pathway plays an important role in HCC tumorigenesis, and ITGB5 may be a promising specific target for HCC therapy.
肿瘤微环境对于癌症的进展和转移至关重要。整合素-β5（ITGB5）是整合素家族的一员，据报道它介导细胞与细胞外基质（ECM）的相互作用，并促进几种恶性肿瘤的发生。然而，ITGB5 在肝细胞癌（HCC）中的作用尚不清楚。
使用迁移、集落形成测定法研究了 ITGB5 在 HCC 中的生物学功能。通过 Western blot、免疫共沉淀和泛素化测定法研究了 ITGB5 调节 HCC 肿瘤发生和β-catenin 稳定的潜在分子机制。通过生物信息学分析、荧光素酶测定证实了 ITGB5 受 miR-185 调节的表达水平。根据人类组织微阵列（TMA）分析确定了 ITGB5 的临床意义。
在这里，我们发现 ITGB5 的表达在 HCC 组织中增加。升高的 ITGB5 明显促进 HCC 细胞在体外和体内的迁移和肿瘤发生。进一步的机制研究表明，ITGB5 作为β-catenin 的伴侣，直接与β-catenin 相互作用并抑制其降解，从而导致 WNT/β-catenin 活性。随后，我们还发现 ITGB5 是 miR-185 的直接靶向基因。HCC 细胞中 miR-185 的下调促进 ITGB5 的增加。ITGB5 的额外增加与 HCC 组织中β-catenin 的上调和 miR-185 的减少有关。
我们的数据表明，miR-185-ITGB5-β-catenin 通路在 HCC 肿瘤发生中起重要作用，ITGB5 可能是 HCC 治疗的有前途的特定靶点。
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