| Summary: | 博士 === 國立陽明大學 === 臨床醫學研究所 === 105 === Tumors growth is influenced by a microenvironment rich in inflammatory cytokines, growth factors and chemokines. Interleukin-6 (IL-6) has also been reported to be associated with tumor progression and chemoresistance in different types of cancers. In our study, we demonstrate that IL-6 enriches the properties of lung CSCs by enhancing cell proliferation through downregulation of p53 and p21. IL-6 also increases DNA methylation and the expression of DNA methyltransferase 1 (DNMT1) in lung CSCs. Knockdown of DNMT1 eliminated IL-6-mediated hypermethylation of cell cycle regulators p53 and p21. Upon blockage of the IL-6/JAK2/STAT3 pathway and inhibition of DNMT1, the proliferation of lung CSCs is reduced and their formation of spheres and ability to initiate tumor growth are decreased. These data suggest that targeting of the IL-6/JAK2/STAT3 signaling pathway and DNMT1 may become important strategies for treating lung cancer.
Tumour-initiating cells (TICs) have the capacity to survive under suspension conditions, while other cells undergo anoikis. Here we show that TICs exhibit increased phosphorylation levels of S727STAT3 because of PP2A inactivation. Collagen XVII (Col XVII) gene expression is upregulated in a STAT3-dependent manner, which also stabilizes laminin-5 and engages cells to form hemidesmosome-like junctions in response. Blocking the PP2A-S727STAT3-Col XVII pathway inhibits the suspension survival of TICs and their ability to form tumours in mice, while activation of the same pathway increases the suspension survival and tumour-initiation capacities of bulk cancer cells. The S727STAT3 phosphorylation levels correlate with Col XVII expression in colon tumour samples, and correlate inversely with survival. This signaling axis also enhances the ability of TIC to form tumours in mouse models of malignant lung cancer pleural effusion and spontaneous colon cancer metastasis.
Epithelial-to-mesenchymal transition (EMT) is associated with metastasis and tumorigenesis in cancer stem-like cells (CSCs) but the underlying mechanism is not clear. We used microarray analysis to identify that Col XVII is one of candidate genes responsible for EMT in lung cancer cells cultured in spheroid and monolayer system. We show that Col XVII is required for maintenance of EMT phenotypes and metastasis ability in lung CSCs. We also show that Col XVII stabilizes laminin-5 to activate the FAK/AKT/GSK3β pathway, thereby suppressing Snail ubiquitination-degradation. The function of Col XVII is mainly dependent on shedding by ADAM9 and ADAM10. Patients who underwent surgical resection for lung cancer, and displayed overexpression of both Col XVII and laminin-5, had the worst prognosis of all expression types. Moreover, blockage of the Col XVII/laminin-5 pathway reduces the EMT phenotypes of lung CSCs in vitro and decreases the potential of lung metastasis in vivo. Our findings suggest that targeting Col XVII and laminin-5 could be novel therapeutic strategies for treating lung cancer patients, and warrant further investigation.
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