Caveolin-1 promotes gastric cancer progression by up-regulating epithelial to mesenchymal transition by crosstalk of signalling mechanisms under hypoxic condition.
Gastric cancer is the second most fatal common form of cancer. The crosstalk among signalling pathways that results in the acceleration of epithelial to mesenchymal transition (EMT) plays a pivotal role in the molecular mechanism of gastric carcinogenesis. To understand the role of caveolin-1 (Cav-1), the expression pattern was studied in human gastric adenocarcinoma tissues and also in AGS and KATO III cell lines. Here, we show that during hypoxic condition, the increase in the levels of hypoxia-inducible factor-1α (HIF-1α) results in a significant decrease in the expression of caveolin-1 which is regulated by heat shock protein 90 (HSP90). The reduced levels of Cav-1 correlated with the increased epidermal growth factor receptor (EGFR) activation resulting in the significant activation of its downstream target STAT3. Accumulation of pSTAT3 in the nucleus results in the decreased expression of E-cadherin and increased expression of mesenchymal markers (Slug, α-SMA, N-cadherin and vimentin). Crosstalk of EGFR and transforming growth factor β (TGF-β) signalling with Wnt signalling enhances cell proliferation, cell survival and upregulates EMT. There was no significant alteration in the expression of epithelial and mesenchymal molecules in both the cell lines studied. Thus, we provide evidence that Cav-1 was modulated by HSP90 and functions as a crucial regulator of EMT in gastric cancer.
Department of Biochemistry, School of Life Sciences, University of Madras, Guindy Campus, Chennai 600025, Tamilnadu, India.
Anbarasu
A
Kannan
Department of Gastroenterology, Madras Medical College, Chennai, Tamilnadu, India.
Arunkumar
A
Krishnan
Department of Gastroenterology, Madras Medical College, Chennai, Tamilnadu, India.
Mohammed
M
Ali
Department of Biochemistry, Apollo Hospitals and Research Centre, Chennai, Tamilnadu, India.
Shyama
S
Subramaniam
Department of Zoology, School of Life Sciences, University of Madras, Guindy Campus, Chennai 600025, Tamilnadu, India.
Devaraj
D
Halagowder
Department of Biochemistry, School of Life Sciences, University of Madras, Guindy Campus, Chennai 600025, Tamilnadu, India. Electronic address: niranjali@yahoo.com.
Niranjali Devaraj
ND
Sivasithamparam
D051242:Caveolin 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D048708:Cell Growth Processes / Q000502:physiology; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015854:Up-Regulation
D051242:Caveolin 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit
Cav-1; Caveolae; Caveolin-1; DPX; Dibutyl Phthalate Xylene; EGFR; EMT; Epithelial to mesenchymal transition; FITC; Fluorescein isothiocyanate; Gastric cancer; PVDF; Phosphorylated Signal transducer and activator of transcription 3; TGF β; caveolin-1; epidermal growth factor receptor; epithelial to mesenchymal transition; pSMAD3; pSTAT3; phosphorylated Mothers against decapentaplegic homolog 3; polyvinyl difluoride; transforming growth factor β.