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TRPM7 overexpression enhances the cancer stem cell-like and metastatic phenotypes of lung cancer through modulation of the Hsp90?/uPA/MMP2 signaling pathway.

ABSTRACT: BACKGROUND:Waixenicin A, a bioactive extract of soft coral Sarcothelia edmondsoni, has been shown to be anti-neoplastic. However, its mechanisms of action remain unclear. Cancer stem cells (CSCs) and associated stemness factors are implicated in lung cancer. Here, we investigated the role of Waixenicin A on CSCs-like and metastatic lung cancer cells. METHODS:We demonstrated and compared TRPM7 expression in the non-tumor lung tissues or bronchial epithelial 16-HBE cell line. TRPM7 was aberrantly expressed in the cancer tissues and SPCA-1, NCI-H520, SK-MES-1, A549 and 95D cell lines. RESULTS:Increased TRPM7 expression was associated with enhanced SOX2, KLF4, and CD133, Hsp90?, uPA, and MMP2 expression in lung cancer cells. TRPM7-silencing inhibited epithelial-to-mesenchymal transition (EMT), suppressed stemness markers and phenotypes, concomitantly suppressed Hsp90?/uPA/MMP2 axis. Coincidently, Waixenicin A treatment downregulated TRPM7 and oncogenic markers; Waixenicin A also attenuated the ability of lung cancer cells to form tumorspheres, in vitro. In validation, our clinicopathological analyses showed that a higher TRPM7 expression was positively correlated with the larger tumor size (p?=?0.007), positive lymph node metastasis (p?=?0.005) and disease grade (p?=?0.003). CONCLUSIONS:Through its ability to inhibit Hsp90?/uPA/MMP2 signaling and suppress TRPM7 expression, we showed that Waixenicin A is a potential anticancer therapeutic agent for treating malignant lung cancer.

SUBMITTER: Liu K

PROVIDER: S-EPMC6258145 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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TRPM7 overexpression enhances the cancer stem cell-like and metastatic phenotypes of lung cancer through modulation of the Hsp90α/uPA/MMP2 signaling pathway.

Liu Kai K Xu Shao-Hua SH Chen Zhao Z Zeng Qing-Xin QX Li Zhi-Jun ZJ Chen Zhou-Miao ZM

BMC cancer 20181126 1

<h4>Background</h4>Waixenicin A, a bioactive extract of soft coral Sarcothelia edmondsoni, has been shown to be anti-neoplastic. However, its mechanisms of action remain unclear. Cancer stem cells (CSCs) and associated stemness factors are implicated in lung cancer. Here, we investigated the role of Waixenicin A on CSCs-like and metastatic lung cancer cells.<h4>Methods</h4>We demonstrated and compared TRPM7 expression in the non-tumor lung tissues or bronchial epithelial 16-HBE cell line. TRPM7 ...[more]

PMID: 30477473

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Project description:The epithelial to mesenchymal transition (EMT) contributes to tumor invasion and metastasis in a variety of cancer types. In human breast cancer, gene expression studies have determined that basal-B/claudin-low and metaplastic cancers exhibit EMT-related characteristics, but the molecular mechanisms underlying this observation are unknown. As the family of miR-200 microRNAs has been shown to regulate EMT in normal tissues and cancer, here we evaluated whether the expression of the miR-200 family (miR-200f) and their epigenetic state correlate with EMT features in human breast carcinomas. We analyzed by qRT-PCR the expression of miR-200f members and various EMT-transcriptional inducers in a series of 70 breast cancers comprising an array of phenotypic subtypes: estrogen receptor positive (ER+), HER2 positive (HER2+), and triple negative (TN), including a subset of metaplastic breast carcinomas (MBCs) with sarcomatous (homologous or heterologous) differentiation. No MBCs with squamous differentiation were included. The DNA methylation status of miR-200f loci in tumor samples were inspected using Sequenom MassArray® MALDI-TOF platform. We also used two non-tumorigenic breast basal cell lines that spontaneously undergo EMT to study the modulation of miR-200f expression during EMT in vitro. We demonstrate that miR-200f is strongly decreased in MBCs compared with other cancer types. TN and HER2+ breast cancers also exhibited lower miR-200f expression than ER+ tumors. Significantly, the decreased miR-200f expression found in MBCs is accompanied by an increase in the expression levels of EMT-transcriptional inducers, and hypermethylation of the miR-200c-141 locus. Similar to tumor samples, we demonstrated that downregulation of miR-200f and hypermethylation of the miR-200c-141 locus, together with upregulation of EMT-transcriptional inducers also occur in an in vitro cellular model of spontaneous EMT. Thus, the expression and methylation status of miR-200f could be used as hypothetical biomarkers to assess the occurrence of EMT in breast cancer.

Dataset Information

TRPM7 overexpression enhances the cancer stem cell-like and metastatic phenotypes of lung cancer through modulation of the Hsp90?/uPA/MMP2 signaling pathway.

Publications

TRPM7 overexpression enhances the cancer stem cell-like and metastatic phenotypes of lung cancer through modulation of the Hsp90α/uPA/MMP2 signaling pathway.

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