Context-dependent effect of sPLA2-IIA induced proliferation on murine hair follicle stem cells and human epithelial cancerResearch in context

Abstract

Background: Tissue stem cells (SCs) and cancer cells proliferation is regulated by many common signalling mechanisms. These mechanisms temporally balance proliferation and differentiation events during normal tissue homeostasis and repair. However, the effect of these aberrant signalling mechanisms on the ultimate fate of SCs and cancer cells remains obscure. Methods: To evaluate the functional effects of Secretory Phospholipase A2-IIA (sPLA2-IIA) induced abnormal signalling on normal SCs and cancer cells, we have used K14-sPLA2-IIA transgenic mice hair follicle stem cells (HFSCs), DMBA/TPA induced mouse skin tumour tissues, human oral squamous cell carcinoma (OSCC) and skin squamous cell carcinoma (SCC) derived cell lines. Findings: Our study demonstrates that sPLA2-IIA induces rapid proliferation of HFSCs, thereby altering the proliferation dynamics leading to a complete loss of the slow cycling H2BGFP positive HFSCs. Interestingly, in vivo reversion study by JNK inhibition exhibited a significant delay in post depilation hair growth, confirming that sPLA2-IIA promotes HFSCs proliferation through JNK/c-Jun signalling. In a different cellular context, we showed increased expression of sPLA2-IIA in human OSCC and mouse skin cancer tissues. Importantly, a xenograft of sPLA2-IIA knockdown cells of OSCC and SCC cell lines showed a concomitant reduction of tumour volume in NOD-SCID mice and decreased JNK/c-Jun signalling. Interpretation: This study unravels how an increased proliferation induced by a common proliferation inducer (sPLA2-IIA) alters the fate of normal SCs and cancer cells distinctively through common JNK/c-Jun signalling. Thus, sPLA2-IIA can be a potential target for various diseases including cancer. Fund: This work was partly supported by the Indian Council of Medical Research (ICMR-3097) and ACTREC (42) grants. Keywords: Hair follicle stem cells, Proliferation dynamics, C-Jun signalling, Oral squamous cell carcinoma, Secretory phospholipase A2-IIA (sPLA2-IIA)