SIPA1 Is a modulator of HGF/MET induced tumour metastasis via the regulation of tight junction-based cell to cell barrier function

Liu, Chang, Jiang, Wenguo ORCID: https://orcid.org/0000-0002-3283-1111, Zhang, Lijian, Hargest, Rachel ORCID: https://orcid.org/0000-0001-9830-3832 and Martin, Tracey A. ORCID: https://orcid.org/0000-0003-2690-4908 2021. SIPA1 Is a modulator of HGF/MET induced tumour metastasis via the regulation of tight junction-based cell to cell barrier function. Cancers 13 (7) , 1747. 10.3390/cancers13071747

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Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	MDPI
ISSN:	2072-6694
Funders:	This research was funded by the Albert Hung Foundation (CCMRC 2015), Cancer Research Wales Data Availability (WGJ2013) and Statement: the Cardiff The China data Medical presented Scholarship in this study (CCMRC2017). are available
Date of First Compliant Deposit:	8 April 2021
Date of Acceptance:	1 April 2021
Last Modified:	08 May 2023 17:42
URI:	https://orca.cardiff.ac.uk/id/eprint/140385

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