Numb has distinct function in lung adenocarcinoma and squamous cell carcinoma.

Hajime Kikuchi,Masaharu Nishimura,Junko Kikuchi,Yasuhiro Hida,Hirotoshi Dosaka-Akita,Megumi Furuta,Eiki Kikuchi,Kichizo Kaga,Satoshi Oizumi,Jun Sakakibara-Konishi,Ichiro Kinoshita

doi:10.18632/oncotarget.25585

Hajime Kikuchi, Masaharu Nishimura + Show 9 more

Open Access

https://doi.org/10.18632/oncotarget.25585

Copy DOI

Abstract

Some reports suggest that Numb is a potential tumor suppressor. However, its role in non-small cell lung cancer remains unclear. Non-small cell lung cancer comprises two major histological subtypes, adenocarcinoma and squamous cell carcinoma. To investigate the role of Numb in tumorigenesis of lung adenocarcinoma and squamous cell carcinoma, we firstly performed loss-of-function and gain-of-function assays. Moreover, Numb expression was investigated in surgically resected lung adenocarcinoma and squamous cell carcinoma tissues by immunohistochemistry and correlations with prognosis were analyzed. Numb suppressed the proliferation, migration, and invasion of adenocarcinoma cells and inhibited Notch signaling and epithelial-mesenchymal transition in vitro. Numb overexpression also inhibited subcutaneous adenocarcinoma tumor growth. In contrast, Numb promoted the proliferation, migration, and invasion of squamous cell carcinoma cells, but did not induce any consistent changes in Notch signaling. High Numb expression was associated with favorable prognosis in patients with lung adenocarcinoma, but not in those with squamous cell carcinoma. Collectively, our data demonstrate that Numb plays distinct roles in lung adenocarcinoma and squamous cell carcinoma. In lung adenocarcinoma, Numb impairs tumor growth and inhibits the Notch pathway and epithelial-mesenchymal transition, whereas in lung squamous cell carcinoma it may promote proliferation.

Highlights

Lung cancer is a leading cause of cancer death worldwide, and despite remarkable advances in treatment, its incidence is still increasing [1, 2]
We discovered that Numb is a promising prognostic marker for patients with lung ADC
In vitro studies demonstrated that Numb might be an activator of tumorigenesis in lung squamous cell carcinoma (SCC) cells, Numb expression was not associated with overall survival in lung SCC patients

Summary

Introduction

Lung cancer is a leading cause of cancer death worldwide, and despite remarkable advances in treatment, its incidence is still increasing [1, 2]. Non-small cell lung cancer (NSCLC) accounts for >80% of all lung cancers It comprises two major histological types, adenocarcinoma (ADC) and squamous cell carcinoma (SCC). They are thought to originate from unique cells of origin, arise through different initiating oncogenic events, and involve the activation of distinct signaling pathways. KRAS or EGFR gene mutations induce a development of lung ADC in Alveolar type 2 or Clara cells, whereas genomic alteration of TP53, PTEN or SOX2 causes a development of lung SCC in basal, Clara or Alveolar type 2 cells [3,4,5,6]. Targeted therapeutic approaches and the www.oncotarget.com assessment of acquired drug-resistance mechanisms based on histological subtypes of NSCLC would be required

Methods

Results

Conclusion