Role of miRNA dynamics and cytokine profile in governing CD44v6/Nanog/PTEN axis in oral cancer: modulating the master regulators.
Late diagnosis, low therapeutic response, and metastasis are accountable for poor 5-year survival rate of OSCC. These failures are attributed to the existence of "cancer stem cell (CSC)" subpopulation. Hence, it is necessary to identify and understand the mechanism of CSCs in tumor development, metastasis, and chemotherapeutic response. Propelling evidences suggest that microRNA (miRNA)-mediated regulation and cytokines of tumor microenvironment have the ability to modulate CSC signalling pathway; however, their exact mechanism needs to be elucidated. Thus, in this study, we characterized CSC markers and highlighted the miRNA dynamics and cytokine profile regulating these CSCs in a pathway-dependent manner. Our results demonstrated CD44+ subpopulation as tumor-initiating cells with self-renewal capability, tumorigenic growth potential and intrinsic chemoresistance. These tumors exhibited increased expression of CSC markers (CD44v3, CD44v6, Nanog, and Bmi1) and significantly reduced expression of PTEN and ATM in OSCC patients. Pathway analysis of these CSC markers demonstrated a prospective pathway regulated by miRNA and cytokine network. On analyzing these modulators, we observed decreased expression of miRNA542-3p, miRNA34a and miRNA9, and significant upregulation of miRNA21, thus forming an unexplored axis. Cytokine profiling revealed significantly increased levels of IL-6 and IL-8 compared to normals and demonstrated their strong association with CD44v6. Collectively, this study indicates that miR5423p and miR34a targets the CD44v6-Nanog-PTEN axis, thus playing a vital role in regulating the CSC properties. Furthermore, we speculate an impinging role of cytokines IL-6 and IL-8 in regulating this CSC-mediated pathway which can have prognostic and therapeutic implications.
Division of Medicinal Chemistry & Pharmacogenomics, Department of Cancer Biology, The Gujarat Cancer & Research Institute, Ahmedabad, Gujarat, 380016, India.
Shanaya
S
Patel
Division of Medicinal Chemistry & Pharmacogenomics, Department of Cancer Biology, The Gujarat Cancer & Research Institute, Ahmedabad, Gujarat, 380016, India. rakesh.rawal@gcriindia.org.
Rakesh
R
Rawal
D014408:Biomarkers, Tumor / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D009062:Mouth Neoplasms / Q000235:genetics* / Q000473:pathology*; D000071317:Nanog Homeobox Protein / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000473:pathology*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000502:physiology
D014408:Biomarkers, Tumor; C497483:CD44 protein, human; C508606:CXCL8 protein, human; D018960:Hyaluronan Receptors; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; C524940:MIRN21 microRNA, human; C522425:MIRN34 microRNA, human; C572357:MIRN542 microRNA, human; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
CD44 isoforms; Cancer stem cells; Cytokine profile; Oral squamous cell carcinoma; miRNA modulators