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Abstract
Background
Pancreatic cancer (PanCa) is one of the most lethal cancers (survival ~ 12%). As the conventional therapeutic interventions are mostly futile, a deep understanding of the disease pathophysiology is an urgent need. Ion channels, located on cell membrane, contribute significantly to cancer hallmarks, through dysregulation of various ion translocation; however, the fundamental mechanisms remain uncertain.
Methods
To identify these oncochannels in Indian cohort of PanCa, we utilized 450 K data, published in our previous study, and identified potential pathways involved. Their expressions were evaluated using TCGA data and an independent Indian paired patient cohort (n = 20). The top genes were further validated using GEO and ScRNA seq dataset. Potential target ability of KCNJ5 was identified through molecular dynamic based drug designing.
Results
A set of 7 differentially methylated and differentially expressed genes of ion-channel proteins namely KCNJ5, CACNB2, KCNA3, KCNA6, RASA3, GABBR2 and CLIC5 were identified in Indian PanCa cohort only. KCNJ5 was significantly upregulated and associated with worse survival in Indian cohort, whereas downregulated in TCGA and other Caucasians patient populations. Two TFs controlling the KCNJ5 expression are POU2F1 and POU3F1. Few predicted small molecules targeting Kcnj5 are, Amiloride, Vernakalant hydrochloride, Dalfampridine, Glyburide and Levcromakalim. It also showed notable interactions with a steroidal anticancer agent, protodioscin.
Conclusion
An onco-channel gene, KCNJ5 significantly upregulated, and showing adverse survival in highly expressed KCNJ5 group in Indian cohort of PanCa, can be targeted with Amiloride, Vernakalant hydrochloride, Dalfampridine, Glyburide Levcromakalim and protodioscin. This understanding can lead to novel target identification for PanCa therapy development.