Liu Chang, Jiang Wenguo, Zhang Lijian, Hargest Rachel, Martin Tracey A
Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
Peking University School of Oncology and Peking University Cancer Hospital, Fucheng Road, Beijing 100142, China.
Cancers (Basel). 2021 Apr 6;13(7):1747. doi: 10.3390/cancers13071747.
Lung cancer is the leading cause of cancer death. SIPA1 is a mitogen induced GTPase activating protein (GAP) and may hamper cell cycle progression. SIPA1 has been shown to be involved in MET signaling and may contribute to tight junction (TJ) function and cancer metastasis.
Human lung tumour cohorts were analyzed. In vitro cell function assays were performed after knock down of SIPA1 in lung cancer cells with/without treatment. Quantitative polymerase chain reaction (qPCR) and western blotting were performed to analyze expression of HGF (hepatocyte growth factor), MET, and their downstream markers. Immunohistochemistry (IHC) and immunofluorescence (IFC) staining were performed.
Higher expression of SIPA1 in lung tumours was associated with a poorer prognosis. Knockdown of SIPA1 decreased invasiveness and proliferation of in vitro cell lines, and the SIPA1 knockdown cells demonstrated leaky barriers. Knockdown of SIPA1 decreased tight junction-based barrier function by downregulating MET at the protein but not the transcript level, through silencing of Grb2, SOCS, and PKCμ (Protein kinase Cµ), reducing the internalization and recycling of MET. Elevated levels of SIPA1 protein are correlated with receptor tyrosine kinases (RTKs), especially HGF/MET and TJs. The regulation of HGF on barrier function and invasion required the presence of SIPA1.
SIPA1 plays an essential role in lung tumourigenesis and metastasis. SIPA1 may be a diagnostic and prognostic predictive biomarker. SIPA1 may also be a potential therapeutic target for non-small cell lung cancer (NSCLC) patients with aberrant MET expression and drug resistance.
肺癌是癌症死亡的主要原因。SIPA1是一种丝裂原诱导的GTP酶激活蛋白（GAP），可能会阻碍细胞周期进程。已表明SIPA1参与MET信号传导，并可能有助于紧密连接（TJ）功能和癌症转移。
分析了人类肺癌队列。在用/不用处理敲低肺癌细胞中的SIPA1后进行体外细胞功能测定。进行定量聚合酶链反应（qPCR）和蛋白质印迹分析以分析肝细胞生长因子（HGF）、MET及其下游标志物的表达。进行免疫组织化学（IHC）和免疫荧光（IFC）染色。
肺癌组织中SIPA1的高表达与较差的预后相关。敲低SIPA1可降低体外细胞系的侵袭性和增殖，并且SIPA1敲低的细胞表现出屏障渗漏。敲低SIPA1通过在蛋白质水平而非转录水平下调MET，通过沉默Grb2、SOCS和蛋白激酶Cμ（PKCμ），减少MET的内化和再循环，从而降低基于紧密连接的屏障功能。SIPA1蛋白水平的升高与受体酪氨酸激酶（RTK）相关，尤其是HGF/MET和紧密连接。HGF对屏障功能和侵袭的调节需要SIPA1的存在。
SIPA1在肺癌发生和转移中起重要作用。SIPA1可能是一种诊断和预后预测生物标志物。SIPA1也可能是MET表达异常和耐药的非小细胞肺癌（NSCLC）患者的潜在治疗靶点。
