Paxillin promotes tumor progression and predicts survival and relapse in oral cavity squamous cell carcinoma by microRNA-218 targeting

Abstract

High-risk human papillomavirus (HPV) 16-infected oral cavity squamous cell carcinoma (OCSCC) differs significantly from non-HPV-infected OCSCC. However, the molecular pathogenesis of HPV-infected OCSCC remains unclear. Paxillin (PXN) has been reported to promote lung tumor progression by miR-218 targeting. In addition, expression of miR-218 has been shown to be reduced by HPV16 E6 in cervical cancer. We thus asked whether PXN can promote tumor progression by E6-reduced miR-218 in OCSCC, especially in HPV-infected OCSCC. Mechanistic studies demonstrated that PXN expression increased markedly upon E6-mediated reductions in miR-218, resulting in increased colony formation and invasion capabilities in HPV-infected OCSCC cells. Among tumor specimens, HPV16/18 infection was negatively associated with miR-218 expression and positively associated with PXN expression. Kaplan-Meier and Cox regression models demonstrated that patients with low-miR-218 tumors or high-PXN tumors exhibited shorter overall survival (OS) and relapse-free survival (RFS) than those with high-miR-218 tumors or low-PXN tumors. Interestingly, HPV-infected patients with low-miR-218, high-PXN tumors and both combinations exhibited the worst OS and RFS compared with patients in their counterparts. These observations in patients were consistent with the findings from the cell model. Therefore, we suggest that PXN might be targeted to suppress tumor progression and consequently to improve outcomes in OCSCC, especially in HPV-infected OCSCC.

HPV strain distribution in patients with genital warts in a female population sample

“…Chemically-induced pro-tumoral factors, drugs and environmental milieu (25), represent another domain that could explain HPV + -triggering conditions. Last but not least, the omics domain (26) may bring additional data into this field, as there are data showing a pro-tumoral association of HPV + lesions with miRNA profiles and/or particular proteomics patterns (27). …”

Paxillin functions as an oncogene in human gliomas by promoting cell migration and invasion

“…Accumulating studies have reported that paxillin may be implicated into the pathogenesis of diverse human malignancies. For example, German et al24 showed that paxillin could promote tumor angiogenesis by regulating the expression of neuropilin 2; Mackinnon et al25 found the overexpression of paxillin in premalignant areas of hyperplasia, squamous metaplasia and goblet cell metaplasia, as well as dysplastic lesions and carcinoma in high-risk patients; Wu et al26,27 further reported that paxillin upregulation induced by miR-218 suppression might be an independent predictor of survival and relapse in nonsmall cell lung cancer and oral cavity squamous cell carcinoma; Xiao et al28 reported that paxillin was strongly expressed in gastric adenoma compared with that in nonneoplastic mucosa and carcinoma, and also found that the aberrant expression of paxillin might be implicated into the differentiation, growth and metastasis of gastric carcinoma and Sen et al29 indicated that paxillin regulated prostate cancer proliferation by serving as a mediator between extranuclear kinase signaling and intranuclear transcriptional signals. Consistent with these previous findings, our data revealed the overexpression of paxillin mRNA and protein in human glioma tissues compared to that in normal brain tissues and found an increasing tendency of paxillin expression from grade I to grade IV.…”

“…Accumulating studies have investigated the underlying mechanisms of paxillin in carcinogenesis and cancer progression of various malignancies 24,26,27,29. However, the mechanism of action on how paxillin expression impacts human gliomas remains unclear.…”

PKCε-mediated c-Met endosomal processing directs fluctuant c-Met-JNK-paxillin signaling for tumor progression of HepG2

“…Paxillin [48][49][50] and JNK [51,52] are currently two of the well known focal adhesion signaling components involved in tumor progression. Previously, the positive effect of JNK on regulating paxillin phosphorylation for tumor progression has been demonstrated [28], and inhibition of the JNK activity significantly reduced the migration rates of HCC cells via attenuation of paxillin phosphorylation at Ser178 [53].…”