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Integrin ?5 contributes to the tumorigenic potential of breast cancer cells through the Src-FAK and MEK-ERK signaling pathways.

ABSTRACT: Cancer progression, response to therapy and metastasis depend on tumor microenvironment. Integrins are cell-adhesion receptors that mediate interactions of cells with extracellular matrix. The ?v-?-family of integrins contributes to tumorigenesis, response to therapy and cancer stem cell biology. Thus, understanding the function of specific integrins in cancer is critical for the development of therapeutic approaches targeting integrins. The study investigated the role of integrin ?5 in breast carcinomas by depleting integrin ?5 using RNA interference and reexpression of integrin ?5. Depletion of integrin ?5 in triple-negative breast carcinoma cells markedly reduced tumor take, growth and tumor angiogenesis, whereas reexpression of integrin ?5 rescued this phenotype. Reduction in tumor angiogenesis is associated with lower expression of vascular endothelial growth factor-A in integrin ?5-depleted tumors. Tumor cells deficient in integrin ?5 have lower migration and proliferative capacities. Biochemical assays revealed that integrin ?5 mediates the Src-focal adhesion kinase and MEK-extracellular signal-regulated kinase signaling events that operate independently, and inhibition of these pathways phenocopies integrin ?5 deficiency. Breast carcinoma cells express high levels of integrin ?5, whereas expression of integrin ?3 is limited to stromal compartments and integrin ?6 is lost in metastatic cells. Together, these findings show a critical role for integrin ?5 in the tumorigenic potential of breast carcinoma cells and therapeutic targeting of integrin ?5 is especially attractive for triple-negative breast carcinomas, which are refractory to most of the current therapies.

SUBMITTER: Bianchi-Smiraglia A

PROVIDER: S-EPMC3481019 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Integrin β5 contributes to the tumorigenic potential of breast cancer cells through the Src-FAK and MEK-ERK signaling pathways.

Bianchi-Smiraglia A A Paesante S S Bakin A V AV

Oncogene 20120723 25

Cancer progression, response to therapy and metastasis depend on tumor microenvironment. Integrins are cell-adhesion receptors that mediate interactions of cells with extracellular matrix. The αv-β-family of integrins contributes to tumorigenesis, response to therapy and cancer stem cell biology. Thus, understanding the function of specific integrins in cancer is critical for the development of therapeutic approaches targeting integrins. The study investigated the role of integrin β5 in breast c ...[more]

PMID: 22824793

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Project description:BackgroundThe development of drug resistance in oral squamous cell carcinoma (OSCC) that frequently leads to recurrence and metastasis after initial treatment remains an unresolved challenge. Presence of cancer stem cells (CSCs) has been increasingly reported to be a critical contributing factor in drug resistance, tumor recurrence and metastasis. Thus, unveiling of mechanisms regulating CSCs and potential targets for developing their inhibitors will be instrumental for improving OSCC therapy.MethodssiRNA, shRNA and miRNA that specifically target keratin 17 (KRT17) were used for modulation of gene expression and functional analyses. Sphere-formation and invasion/migration assays were utilized to assess cancer cell stemness and epithelial mesenchymal transition (EMT) properties, respectively. Duolink proximity ligation assay (PLA) was used to examine molecular proximity between KRT17 and plectin, which is a large protein that binds cytoskeleton components. Cell proliferation assay was employed to evaluate growth rates and viability of oral cancer cells treated with cisplatin, carboplatin or dasatinib. Xenograft mouse tumor model was used to evaluate the effect of KRT17- knockdown in OSCC cells on tumor growth and drug sensitization.ResultsSignificantly elevated expression of KRT17 in highly invasive OSCC cell lines and advanced tumor specimens were observed and high KRT17 expression was correlated with poor overall survival. KRT17 gene silencing in OSCC cells attenuated their stemness properties including markedly reduced sphere forming ability and expression of stemness and EMT markers. We identified a novel signaling cascade orchestrated by KRT17 where its association with plectin resulted in activation of integrin β4/α6, increased phosphorylation of FAK, Src and ERK, as well as stabilization and nuclear translocation of β-catenin. The activation of this signaling cascade was correlated with enhanced OSCC cancer stemness and elevated expression of CD44 and epidermal growth factor receptor (EGFR). We identified and demonstrated KRT17 to be a direct target of miRNA-485-5p. Ectopic expression of miRNA-485-5p inhibited OSCC sphere formation and caused sensitization of cancer cells towards cisplatin and carboplatin, which could be significantly rescued by KRT17 overexpression. Dasatinib treatment that inhibited KRT17-mediated Src activation also resulted in OSCC drug sensitization. In OSCC xenograft mouse model, KRT17 knockdown significantly inhibited tumor growth, and combinatorial treatment with cisplatin elicited a greater tumor inhibitory effect. Consistently, markedly reduced levels of integrin β4, active β-catenin, CD44 and EGFR were observed in the tumors induced by KRT17 knockdown OSCC cells.ConclusionsA novel miRNA-485-5p/KRT17/integrin/FAK/Src/ERK/β-catenin signaling pathway is unveiled to modulate OSCC cancer stemness and drug resistance to the common first-line chemotherapeutics. This provides a potential new therapeutic strategy to inhibit OSCC stem cells and counter chemoresistance.

Dataset Information

Integrin ?5 contributes to the tumorigenic potential of breast cancer cells through the Src-FAK and MEK-ERK signaling pathways.

Publications

Integrin β5 contributes to the tumorigenic potential of breast cancer cells through the Src-FAK and MEK-ERK signaling pathways.

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