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

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 A 2-IIA (sPLA 2-IIA) induced abnormal signalling on normal SCs and cancer cells, we have used K14-sPLA 2-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 sPLA 2-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 sPLA 2-IIA promotes HFSCs proliferation through JNK/c-Jun signalling. In a different cellular context, we showed increased expression of sPLA 2-IIA in human OSCC and mouse skin cancer tissues. Importantly, a xenograft of sPLA 2-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 (sPLA 2-IIA) alters the fate of normal SCs and cancer cells distinctively through common JNK/c-Jun signalling. Thus, sPLA 2-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.

Group IIA secreted phospholipase A2 controls skin carcinogenesis and psoriasis by shaping the gut microbiota

“…Lastly, considering that sPLA 2 -IIA is expressed in human skin ( 36 , 84 ), translation of our present study to human skin pathology is not so simple, since we need to think of the skin-intrinsic roles of sPLA 2 -IIA and the extrinsic effects of the intestinal sPLA 2 -IIA/microbiota axis, both of which can be variably influenced by environmental factors. Nevertheless, in the context of skin cancer, our results have raised the possibility that the elevated levels of sPLA 2 -IIA in human feces might have predictive values for the disease.…”

“…Intestinal sPLA 2 -IIA expression is regulated by gut microbiota. Reportedly, skin-specific mouse sPLA 2 -IIA Tg mice (K14-Pla2g2a TGN ) showed increased skin carcinogenesis (35), and PLA2G2A knockdown in human skin squamous cell carcinoma reduced tumorigenesity (36). Beyond these skin-intrinsic actions of sPLA 2 -IIA in Tg mice and humans, however, the present finding that Pla2g2a -/mice displayed a skin phenotype was surprising, since it has been reported that sPLA 2 -IIA is expressed almost exclusively in Paneth cells in the small intestine of BALB/c mice (25,26,29).…”

Phospholipase A2 enzymes represent a shared pathogenic pathway in psoriasis and pityriasis rubra pilaris

“…Moreover, sPLA2 enhances Toll-like receptor activity, as it can increase the intracellular uptake of poly(I:C), inducing phosphorylation of NF-κB and mitogen-activated protein kinases (MAPKs) in keratinocytes ( 38 ). Another PLA2, sPLA2-IIA, regulates the proliferation of tissue stem cells and cancer cells through common JNK/c-Jun signaling, thus contributing to tissue homeostasis and repair ( 39 ). Therefore, the mechanism underlying PLA2s’ regulation of the immune response in keratinocytes warrants further investigations.…”

Updating Phospholipase A2 Biology

“…PLA2G2A -transgenic mice display notable skin abnormalities with hair loss and epidermal hyperplasia [ 27 ]. Using K14 -driven, skin-specific PLA2G2A -transgenic mice, Chovatiya et al [ 28 ] recently demonstrated that sPLA 2 -IIA promotes hair follicle stem cell proliferation through JNK signaling and that sPLA 2 -IIA-knockdown skin cancers xenografted into NOD-SCID mice show a concomitant reduction of tumor volume and decreased JNK signaling. Kuefner et al [ 29 ] showed that PLA2G2A -transgenic mice are protected from diet-induced obesity and become more prone to adipocyte browning with increased expression of thermogenic markers.…”