Carboxyl-Terminal Modulator Protein Positively Acts as an Oncogenic Driver in Head and Neck Squamous Cell Carcinoma via Regulating Akt phosphorylation.

Jae Won Chang,Jongsun Park,Bon Seok Koo,Lihua Liu,Seung-Nam Jung,Jin Man Kim,Ju-Hee Kim,Hee Sung Park,Geun-Ae Shim

doi:10.1038/srep28503

Jae Won Chang, Jongsun Park + Show 7 more

Open Access

https://doi.org/10.1038/srep28503

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Journal: Scientific Reports	Publication Date: Jun 1, 2016
Citations: 13	License type: CC BY 4.0

Affiliation: Chungnam National University

Abstract

The exact regulatory mechanisms of carboxyl-terminal modulator protein (CTMP) and its downstream pathways in cancer have been controversial and are not completely understood. Here, we report a new mechanism of regulation of Akt serine/threonine kinase, one of the most important dysregulated signals in head and neck squamous cell carcinoma (HNSCC) by the CTMP pathway and its clinical implications. We find that HNSCC tumor tissues and cell lines had relatively high levels of CTMP expression. Clinical data indicate that CTMP expression was significantly associated with positive lymph node metastasis (OR = 3.8, P = 0.033) and correlated with poor prognosis in patients with HNSCC. CTMP was also positively correlated with Akt/GSK-3β phosphorylation, Snail up-regulation and E-cadherin down-regulation, which lead to increased proliferation and epithelial-to-mesenchymal transition, suggesting that CTMP expression results in enhanced tumorigenic and metastatic properties of HNSCC cells. Moreover, CTMP suppression restores sensitivity to cisplatin chemotherapy. Intriguingly, all the molecular responses to CTMP regulation are identical regardless of p53 status in HNSCC cells. We conclude that CTMP promotes Akt phosphorylation and functions as an oncogenic driver and prognostic marker in HNSCC irrespective of p53.

Highlights

Tumors expressing a hallmark of epithelial-to-mesenchymal transition (EMT) has a twofold increase in the metastasis compared to primary tumors without an EMT signature[7,8]
We assessed whether carboxyl-terminal modulator protein (CTMP) expression varied between normal and tumor tissue derived from the same patients at mRNA and protein levels
RT-PCR and Western blot analysis revealed that tumor tissues had higher CTMP expressions at both mRNA and protein levels compared to normal tissues (Fig. 1B,C)

Summary

Introduction

Tumors expressing a hallmark of EMT has a twofold increase in the metastasis compared to primary tumors without an EMT signature[7,8]. Given that Akt signaling plays important roles in tumorigenesis and metastatic progression, by regulating apoptosis, as well as in cell cycling, protein synthesis, and glucose metabolism, understanding the role of CTMP in HNSCC may lead to new therapeutic targets. Since PI3K/Akt activation is correlated with cisplatin resistance in HNSCC14, determining the relationship between CTMP and Akt regulation may contribute to our understanding of HNSCC chemoresistance. We addressed CTMP expression and its role in Akt signaling during HNSCC development and progression were investigated using an in vitro functional assays and tissue microarray (TMA) expression analysis in different HNSCC patient cohorts. We aimed to determine whether CTMP expression could serve as a prognostic marker for tumor response to platinum-based chemotherapy

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