S100A6 promotes cell proliferation in human nasopharyngeal carcinoma via the p38/MAPK signaling pathway

Abstract

An elevated level of S100A6 is associated with poor outcomes of many tumor types, but, how S100A6 contributes to nasopharyngeal carcinoma (NPC) progression remains unknown. Here, we investigated the expression and prognostic significance of S100A6 in NPC and explored the molecular mechanisms under-lying the role of S100A6 in NPC development. The results showed that S100A6 was markedly up-regulated in NPC tissues and cell lines compared to paired peritumoral normal tissues and a normal nasopharyngeal epithelial cell line, respectively. In tissues from 92 NPC patients, high S100A6 expression was associated with advanced N stage, locoregional failure and disease progression and was predictive of poor locoregional recurrence-free survival (LRRFS, P = 0.001) and progression-free survival (PFS, P = 0.001). Multivariate analysis showed that S100A6 is an independent prognostic factor for LRRFS and PFS. Silencing S100A6 using siRNA or shRNA significantly suppressed NPC cell proliferation, colony formation and p38/mitogen-activated protein kinase (MAPK) activity in vitro and inhibited tumor growth in a xenograft mouse model of NPC. In contrast, overexpressing S100A6 via plasmid transfection resulted in increased NPC cell proliferation and p38/MAPK activation. S100A6-induced proliferation was abolished by a p38 inhibitor. In summary, S100A6 may be a new prognostic marker of NPC and may promote NPC development via the activation of p38/MAPK signaling pathways. These findings suggest S100A6/p38/MAPK signaling as a potential therapeutic target for NPC. © 2016 Wiley Periodicals, Inc.

An FGFR 3/ MYC positive feedback loop provides new opportunities for targeted therapies in bladder cancers

“…p38 can be activated by tyrosine kinase receptors (PDGF receptor, VEGF receptor, EGF receptor, FGFR1) to function as a positive regulator of tumor progression, mediating motility and invasion, suppressing apoptosis, stimulating the epithelial‐to‐mesenchymal transition in various cell types (Bates & Mercurio, ; Frey et al , ; Nishihara et al , ). Our results demonstrating that p38α promotes proliferation, by upregulating MYC mRNA levels are in line with the protumorigenic functions of p38 and with recent studies in breast, head and neck cancers and nasopharyngeal carcinoma (Leelahavanichkul et al , ; Li et al , ; Wada et al , ). The activation of p38 by activated‐FGFR3 in bladder tumors contributes to malignant behavior and the inhibition of this activation may be of therapeutic value, as reported for an increasing number of cancers (Koul et al , ; Igea & Nebreda, ).…”

Licochalcone A induces apoptotic cell death via JNK/p38 activation in human nasopharyngeal carcinoma cells

“…Early reports have indicated that MAPK and PI3K pathways are targets for the development of therapeutic agents against nasopharyngeal carcinoma . Recently, S100A6 has been shown to elevate cell proliferation by increasing the levels of the phosphorylated p38 pathway in human nasopharyngeal carcinoma patients . In agreement with this finding, we also observed upregulation of p38 and JNK1/2 phosphorylation in licochalcone A‐treated HONE‐1 cells.…”

“…47 Recently, S100A6 has been shown to elevate cell proliferation by increasing the levels of the phosphorylated p38 pathway in human nasopharyngeal carcinoma patients. 48 In agreement with this finding, we also observed upregulation of p38 and JNK1/2 phosphorylation in licochalcone A-treated HONE-1 cells. The inhibitor of JNK1/2 or p38 significantly attenuated the licochalcone A-induced protein expression of cleaved-caspase-9, cleaved-caspase-8, and cleaved-caspase-3.…”

Cathepsin C Interacts with TNF-α/p38 MAPK Signaling Pathway to Promote Proliferation and Metastasis in Hepatocellular Carcinoma

“…4B). MAPK (p38) pathway plays a crucial role in cell proliferation and metastasis, the inflammatory microenvironment in cancers [22][23][24][25]. In neurological diseases, CTSC was found to induce microglia M1 polarization and promote neuroinflammation via activation of protein kinase C/p38-MAPK/nuclear factor-#B pathway [26].…”