Focal adhesion kinase (FAK) is a cytoplasmic nonreceptor tyrosine kinase that enables activation by growth factor receptors or integrins in various types of human cancers. The kinase-dependent and kinase-independent scaffolding functions of FAK modulate the authentic signaling and fundamental functions not only in cancer cells but also in tumor microenvironment to facilitate cancer progression and metastasis. The overexpression and activation of FAK are usually investigated in primary or metastatic cancers and correlated with the poor clinical outcome, highlighting FAK as a potential prognostic marker and anticancer target. Small molecule inhibitors targeting FAK kinase activity or FAK-scaffolding functions impair cancer development in preclinical or clinical trials. In this review, we give an overview for FAK signaling in cancer cells as well as tumor microenvironment that provides new strategies for the invention of cancer development and malignancy.

Inflammasomes sense infection and cellular damage and are critical for triggering inflammation through IL-1β production. In carcinogenesis, inflammasomes may have contradictory roles through facilitating antitumour immunity and inducing oncogenic factors. Their function in cancer remains poorly characterized. Here we show that the NLRP3, AIM2 and RIG-I inflammasomes are overexpressed in Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC), and expression levels correlate with patient survival. In tumour cells, AIM2 and RIG-I are required for IL-1β induction by EBV genomic DNA and EBV-encoded small RNAs, respectively, while NLRP3 responds to extracellular ATP and reactive oxygen species. Irradiation and chemotherapy can further activate AIM2 and NLRP3, respectively. In mice, tumour-derived IL-1β inhibits tumour growth and enhances survival through host responses. Mechanistically, IL-1β-mediated anti-tumour effects depend on infiltrated immunostimulatory neutrophils. We show further that presence of tumour-associated neutrophils is significantly associated with better survival in NPC patients. Thus, tumour inflammasomes play a key role in tumour control by recruiting neutrophils, and their expression levels are favourable prognostic markers and promising therapeutic targets in patients.

The inflammasome adaptor protein, ASC, contributes to both innate immune responses and inflammatory diseases via self-oligomerization, which leads to the activation of the protease, caspase-1. Here, we report that the cytosolic tyrosine kinases, FAK and Pyk2, are differentially involved in NLRP3 and AIM2 inflammasome activation. The inhibition of FAK and Pyk2 with RNA interference or chemical inhibitors dramatically abolished ASC oligomerization, caspase-1 activation, and IL-1β secretion in response to NLRP3 or AIM2 stimulation. Pyk2 is phosphorylated by the kinase Syk and relocalizes to the ASC specks upon NLRP3 inflammasome activation. Pyk2, but not FAK, could directly phosphorylate ASC at Tyr146, and only the phosphorylated ASC could participate in speck formation and trigger IL-1β secretion. Moreover, the clinical-trial-tested Pyk2/FAK dual inhibitor PF-562271 reduced monosodium urate-mediated peritonitis, a disease model used for studying the consequences of NLRP3 activation. Our results suggest that although Pyk2 and FAK are involved in inflammasome activation, only Pyk2 directly phosphorylates ASC and brings ASC into an oligomerization-competent state by allowing Tyr146 phosphorylation to participate ASC speck formation and subsequent NLRP3 inflammation.

Purpose: Heterogeneous ribonucleoprotein K (hnRNP K) regulates thymidine phosphorylase (TP) mRNA stability. The aim of the present study was to analyze hnRNP K and TP expression in nasopharyngeal carcinoma (NPC) and to evaluate the prognostic and therapeutic potential of these two markers. Experimental Design: We analyzed hnRNP K and TP expression immunohistochemically in 121 clinically proven NPC cases. Statistical analyses were applied to correlate cytoplasmic hnRNP K with elevated TP expression and determine the prognostic significance of these parameters. The therapeutic implication of elevatedTP expression was determined by measuring sensitivity of NPC cells to theTP-targeting drug, 5-fluoro-5 ¶-deoxyuridine (5 ¶-DFUR).Results: There was a high correlation between cytoplasmic hnRNP K and high TP (P < 0.001).Both cytoplasmic hnRNP K and high TP were associated with poor overall survival (OS; P = 0.007 and P < 0.001, respectively) and distant metastasis-free survival (P = 0.003 and 0.001, respectively) of NPC patients. A multivariate analysis confirmed that both cytoplasmic hnRNP K and high TP are independent prognostic predictors for OS (P = 0.020 and 0.010, respectively). NPC cells expressing highTP were more sensitive to treatment with theTP-targeting drug, 5 ¶-DFUR. Conclusions: Cytoplasmic hnRNP K and high TP are associated with shorter OS and distant metastasis-free survival in NPC patients. In vitro experiments suggest that NPC tumors with high TP expression may be sensitive to 5 ¶-DFUR treatment. Cytoplasmic hnRNP K and high TP may be potential prognostic and therapeutic markers for NPC, but additional validation studies are warranted.

Tumor necrosis factor alpha (TNFa) is an inflammatory cytokine that is present in the microenvironment of many tumors and is known to promote tumor progression. To examine how TNFa modulates the progression and metastasis of nasopharyngeal carcinoma, we used Affymetrix chips to identify TNFa-inducible genes that are dysregulated in this tumor. Elevated expression of TNFAIP2, which encodes TNFa-inducible protein 2 and not previously known to be associated with cancer, was found and confirmed by quantitative RT-PCR of TNFAIP2 expression in nasopharyngeal carcinoma and adjacent normal tissues. Immunohistochemical analysis showed that the TNFAIP2 protein was highly expressed in tumor cells. Analysis of 95 nasopharyngeal carcinoma biopsy specimens revealed that high TNFAIP2 expression was significantly correlated with highlevel intratumoral microvessel density (P ¼ 0.005) and low distant metastasis-free survival (P ¼ 0.001). A multivariate analysis further confirmed that TNFAIP2 was an independent prognostic factor for nasopharyngeal carcinoma (P ¼ 0.002). In vitro, TNFa treatment of nasopharyngeal carcinoma HK1 cells was found to induce TNFAIP2 expression, and siRNA-based knockdown of TNFAIP2 dramatically reduced the migration and invasion of nasopharyngeal carcinoma HK1 cells. These results collectively suggest for the first time that TNFAIP2 is a cell migration-promoting protein and its expression predicts distant metastasis. Our data suggest that TNFAIP2 may serve as an independent prognostic indicator for nasopharyngeal carcinoma.