Extranodal NK/T-Cell Lymphoma: Toward the Identification of Clinical Molecular Targets

Extranodal natural killer (NK)/T-cell lymphoma of nasal type (NKTCL) is a malignant disorder of cytotoxic lymphocytes of NK or more rarely T cells associated with clonal Epstein-Barr virus infection. Extranodal NKTCL is rare in Western countries, but in Asia and Central and South America it can account for up to 10% of non-Hodgkin's lymphomas. It is an aggressive neoplasm with very poor prognosis. Although the pathogenesis of extranodal NKTCL remains poorly understood, some insights have been gained in the recent years, especially from genome-wide studies. Based on our own experience and knowledge of the literature, we here review some of the genomic and functional pathway alterations observed in NKTCL that could provide a rationale for the development of innovative therapeutic strategies

Proteome Analyses Reveal Positive Association of COL2A1, MPO, TYMS, and IGFBP5 with Canine Mammary Gland Malignancy

Purpose: To identify aberrantly expressed proteins contributing to pathogenesis of canine mammary tumors (CMTs) which are the most prevalent neoplasms in female dogs and include different types. Experimental design: Frozen tissue specimens of normal mammary gland (n = 7), lobular hyperplasia (n = 6), simple carcinoma (n = 6), and complex carcinoma (n = 6) are collected from 11 CMT cases. Tissue homogenates are comparatively analyzed by the isobaric tags for relative and absolute quantification (iTRAQ) combined with LC-MS/MS to identify proteins differentially expressed in different-type CMT tissues. Results: Among 3795 proteins identified and quantified among all groups, 133, 127, and 98 proteins are particularly overexpressed in simple carcinoma, complex carcinoma, and both types, respectively, compared with normal and hyperplastic tissues. Moreover, collagen type II alpha 1 chain (COL2A), myeloperoxidase (MPO), thymidylate synthetase (TYMS), and insulin-like growth factor-binding protein 5 (IGFBP5) are validated to be highly expressed in different-type CMT tissues using immunoblotting and immunohistochemistry. Notably, COL2A1 and IGFBP5 levels are correlated with clinical stages. Conclusions and clinical relevance: COL2A1, MPO, TYMS, and IGFBP5 protein levels are positively associated with CMT development. Data expedite further investigations to improve treatment regimens for CMT

Activin A regulates the epidermal growth factor receptor promoter by activating the PI3K/SP1 pathway in oral squamous cell carcinoma cells

Abstract Epidermal growth factor receptor (EGFR) and activin A are both overexpressed in oral cavity squamous cell carcinoma (OSCC). We evaluated their clinical correlation and activin A-mediated EGFR regulation in this study. Overexpression of both transcripts/proteins indicated a poorer prognosis in OSCC patients. Knockdown of endogenous INHBA repressed the expression of EGFR and inhibited activin A-mediated canonical Smads, noncanonical phosphorylation of AKT (ser473) (p-AKT ser473) and SP1. Inhibition of PI3K signaling via its inhibitor attenuated p-AKT ser473 and in turn reduced SP1 and EGFR expression in the presence of recombinant activin A (rActivin A) in OSCC cells, as revealed via a luciferase assay and western blotting. However, canonical Smad signaling repressed the EGFR promoter, as revealed by a luciferase assay. The transcription factor SP1, its coactivator CBP/p300, and Smad proteins were recruited to the EGFR proximal promoter following rActivin A treatment, as revealed by chromatin immunoprecipitation (ChIP). Smad2/3/4 dramatically outcompeted SP1 binding to the EGFR proximal promoter following mithramycin A treatment. Activin A activates the PI3K and Smad pathways to compete for binding to overlapping SP1 consensus sequences on the EGFR proximal promoter. Nevertheless, canonical p-Smad2 was largely repressed in OSCC tumor tissues, suggesting that the activin A-mediated noncanonical pathway is essential for the carcinogenesis of OSCC

Discovering the Clinical and Prognostic Role of Pan-Immune-Inflammation Values on Oral Cavity Squamous Cell Carcinoma

A newly introduced pan-immune-inflammation value (PIV) was not evaluated for its role in oral cavity squamous cell carcinoma (OSCC). In this study, the PIV was calculated with the following equation (neutrophil count × platelet count × monocyte count)/lymphocyte count from the results of the automated hematology analyzers in 853 OSCC patients from 2005 to 2017. The optimal cutoff for the preoperative PIV was 268, as determined by a receiver operating characteristic curve. Significant differences were observed for alcohol consumption, smoking, pT status, pN status, overall pathological status, extranodal extension, cell differentiation, depth of invasion, and perineural invasion between higher and lower PIV patients (all p values < 0.05). Kaplan-Meier and univariate regression analyses indicated that higher PIV was associated with worse overall survival, disease-free survival, locoregional recurrence-free survival, and distant metastasis-free survival (all p values < 0.001). Multivariate analyses adjusted by various factors further demonstrated that PIV was an independent prognostic factor for overall and distant metastasis-free survival (p = 0.027, HR: 1.281 and p = 0.031, HR: 1.274, respectively). In conclusion, a higher PIV level was associated with poor clinicopathological factors in OSCC patients and could be used to predict poor posttreatment outcomes, especially for overall and distant metastasis-free survival

Discovering the Clinical and Prognostic Role of Pan-Immune-Inflammation Values on Oral Cavity Squamous Cell Carcinoma

A newly introduced pan-immune-inflammation value (PIV) was not evaluated for its role in oral cavity squamous cell carcinoma (OSCC). In this study, the PIV was calculated with the following equation (neutrophil count × platelet count × monocyte count)/lymphocyte count from the results of the automated hematology analyzers in 853 OSCC patients from 2005 to 2017. The optimal cutoff for the preoperative PIV was 268, as determined by a receiver operating characteristic curve. Significant differences were observed for alcohol consumption, smoking, pT status, pN status, overall pathological status, extranodal extension, cell differentiation, depth of invasion, and perineural invasion between higher and lower PIV patients (all p values p values p = 0.027, HR: 1.281 and p = 0.031, HR: 1.274, respectively). In conclusion, a higher PIV level was associated with poor clinicopathological factors in OSCC patients and could be used to predict poor posttreatment outcomes, especially for overall and distant metastasis-free survival

The interplay between IGF-1R signaling and Hippo-YAP in breast cancer stem cells

Both IGF-1R/PI3K/AKT/mTOR and Hippo pathways are crucial for breast cancer stem cells (BCSCs). However, their interplay remains unclear. Four triple negative breast cancer cell lines derived from CSC of two patient-derived xenografts (PDXs), AS-B145, AS-B145-1R, AS-B244, and AS-B244-1R, were used to elucidate the role of YAP in BCSCs. YAP silenced BCSCs were analyzed by cell proliferation, aldehyde dehydrogenase (ALDH) activity, mammosphere formation, and tumorigenesis. The effects of modulating IGF-1R and IGF-1 on YAP expression and localization were evaluated. The clinical correlation of YAP and IGF-1R signaling with the overall survival (OS) of 7830 breast cancer patients was analyzed by KM plotter. Knockdown of YAP abates the viability and stemness of BCSCs in vitro and tumorigenicity in vivo. Depletion of IGF-1R by shRNA or specific inhibitor decreases YAP expression. In contrast, IGF-1 addition upregulates YAP and enhances its nuclear localization. YAP overexpression increased the mRNA level of IGF-1, but not IGF-1R. Data mining of clinical breast cancer specimens revealed that basal-like breast cancer patients with higher level of IGF-1 and YAP exhibit significantly shorter OS. YAP contributes to stemness features of breast cancer in vitro and in vivo. The expression and localization of YAP was regulated by IGF-1R and YAP expression in turns upregulates IGF-1, but not IGF-1R. Clinically, higher level of YAP and IGF-1 significantly correlated with shorter OS in basal-like breast cancer. Taken together, these findings suggest the clinical relevance of interplay between YAP and IGF-1/IGF-1R pathway in sustaining the properties of BCSCs. Video Abstract