Hepatocyte growth factor (HGF) regulates cell motility, proliferation and morphology and has a crucial impact on the ability of tumors to metastasize. Tight Junctions (TJs) are the first barrier that cancer cells must overcome to metastasize. In previous studies, signal induced proliferation associated protein 1 (SIPA1) has been shown to be involved in the metastasis of tumors. Breast and prostate cancer cells exhibit reduced response to HGF after SIPA1 knock down which was concurrent with changes in the regulation of TJs. It appears that SIPA1 influence HGF mediated control of TJs in cancer cells. We aimed to discover the role of SIPA1 in the HGF-mediated regulation of TJs and metastatic spread in lung adenocarcinoma.
Expression of SIPA1 was measured in human lung tumor tissues (n = 148) together with adjacent background tissue (n = 148). IHC was performed to examine SIPA1 expression within a lung tissue microarray. In vitro cell function assays were carried out after knock down of SIPA1 in the A549 cell line with/without HGF. Related TJs protein expression was analyzed using qPCR and western blotting.
Patients with lung cancer exhibited a higher expression level of SIPA1 in tumor compared with background tissues (n = 148, p = 0.0141). High expression of SIPA1 was associated with advanced T stage of lung cancer (T3 vs T1, p = 0.014) and poor prognosis (p = 0.0021). Moreover, knockdown of SIPA1 reduced the aggressive behavior and enhanced the barrier function of the A549 cells. The SIPA1 knockdown cells showed a decreased response after treatment with HGF in invasion, proliferation and barrier function assays. In addition, receptor of HGF (Met) and several TJ components such as JAM1, Claudin5, Claudin10, Claudin11 and Claudin20 had reduced expression, whilst others such as Claudin1, Claudin19 had increased expression after knockdown of SIPA1.
SIPA1 may act as a targeting molecule and a marker for prognosis in lung adenocarcinoma. It has an effect on pathways associated with aggressive behavior and barrier function in lung cancer cells. HGF induced malignant behavior of cancer cells requires the presence and influence of SIPA1, which can effect changes in cancer cell behavior by interacting with the TJ complex.
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Legal entity responsible for the study
Tracey A. Martin - Cardiff China Medical Research Collaborative, School of Medicine, Cardiff University.
Has not received any funding.
All authors have declared no conflicts of interest.