Upregulation of OTUD7B (Cezanne) Promotes Tumor Progression via AKT/VEGF Pathway in Lung Squamous Carcinoma and Adenocarcinoma.

Dan-Dan Lin,Naipeng Cui,Wen-Wen Liu,Yang Shen,Jian-Hong Shi,Shuli Zhao,Yun-Fan Wang,Ya-Nan Wang,Shu Qiao,Lishuang Zheng

doi:10.3389/fonc.2019.00862

Abstract

OTUD7B, a multifunctional deubiquitinylase, plays an essential role in inflammation and proliferation signals. However, its function in lung cancer remains largely unknown. The aim of this study was to evaluate the prognostic significance of OTUD7B in patients with lung adenocarcinoma and squamous carcinoma and to characterize its molecular mechanisms in lung cancer progression and metastasis. Two tissue microarrays containing 150 pairs of lung squamous carcinoma and matched adjacent non-cancer tissues, and one tissue microarray containing 75 pairs of lung adenocarcinoma and adjacent non-cancer tissues were included, and immunohistochemical staining was performed to assess the clinical relevance of OTUD7B in non-small cell lung cancer. OTUD7B is highly expressed in both lung squamous carcinoma and adenocarcinoma and correlates with a worse prognosis. MTT proliferation, colony formation, migration and invasion assays and immunoblotting assay in NCI-H358 and A549 cell lines suggested that OTUD7B enhances EGF-induced Akt signal transduction and promotes lung cancer cell proliferation and migration. Immunohistochemical staining of large-scale lung cancer subjects (171 cases) revealed positive correlation of OTUD7B and VEGF expression. ELISA and tube formation assay revealed OTUD7B promotes VEGF production and angiogenesis. NCI-H358 tumor model demonstrated OTUD7B is required for lung tumor progression by facilitating activation of Akt signaling. These findings collectively identified OTUD7B as an independent predictive factor for the prognosis of non-small cell lung cancer and revealed OTUD7B promotes lung cancer cell proliferation and metastasis via Akt/VEGF signal pathway.

Highlights

Lung cancer is one of the most common cancers and leading causes of cancer-related deaths worldwide
The OTUD7B gene was frequently amplified in non-small cell lung cancer (NSCLC), including lung squamous carcinoma (LUSC) and lung adenocarcinoma (LAD), according to the The Cancer Genome Atlas (TCGA) DNA sequencing results (Supplementary Figure S1)
IHC analysis revealed that OTUD7B expression was significantly upregulated in both LUSC (Figure 1A) and LAD (Supplementary Figures S2A–D) tissues compared with adjacent tissues

Summary

Introduction

Lung cancer is one of the most common cancers and leading causes of cancer-related deaths worldwide. Ubiquitination is an important mechanism that regulates cancer progression [3, 4]. Deubiquitylases (DUBs) are enzymes that hydrolysis ubiquitin chains from target proteins and contribute to their stabilization and activation [5, 6]. DUBs play essential roles in inflammation and proliferation signal transduction and are considered effective therapeutic targets against lung cancer. OTUD7B, a DUB belonging to A20 subgroup of ovarian tumor (OUT) protein superfamily, functions as an inflammation and NF-κB signaling regulator [7,8,9,10,11]. Accumulate data suggested that OTUB7B appears to be the primary regulatory mechanism to growth signals, including activation of mTORC2/Akt pathway [12], regulation of E2F1dependent HIF2α expression [13], stabilization of HIF1α [14], and EGFR [15]

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