Expression of Notch1 and Numb in small cell lung cancer

Hajime Kikuchi,Hiroshi Nishihara,Fumihiro Tanaka,Shigeo Yamazaki,Yoshinori Minami,Kei Takamura,Satoshi Oizumi,Mitsunori Higuchi,Osamu Honjo,Hidetaka Uramoto,Megumi Furuta,Mitsuru Munakata,Fumiko Sugaya,Naomi Watanabe,Toshiyuki Harada,Masao Harada,Hiroshi Yokouchi,Yuka Fujita,Hiroyuki Suzuki,Masaharu Nishimura,Kenji Akie,Hiroshi Isobe,Takashi Ishida,Jun Sakakibara‐Konishi ,Hirotoshi Dosaka‐Akita ,Takao Kojima

doi:10.18632/oncotarget.14411

Abstract

Notch signaling in tumorigenesis functions as an oncogene or tumor suppressor according to the type of malignancy. Numb represses intracellular Notch signaling. Previous studies have demonstrated that Notch signaling suppresses the proliferation of small cell lung cancer (SCLC) cell lines. However, in SCLC, the association between Notch1 and Numb expression and clinicopathological factors or prognosis has remained unclear. In this study, we evaluated the expression of Notch1 and Numb in SCLC. We immunohistochemically assessed 125 SCLCs that were surgically resected at 16 institutions participating in either the Hokkaido Lung Cancer Clinical Study Group Trial (HOT) or the Fukushima Investigative Group for Healing Thoracic Malignancy (FIGHT) between 2003 and 2013. Correlations between Notch1 or Numb expression and various clinicopathological features were evaluated. Notch1 expression was associated with ECOG performance status. Numb expression was associated with age, sex, and pathological histology (SCLC or Combined SCLC). Analysis of cellular biological expression did not demonstrate a significant correlation between the expression of Notch1 and of Numb. Multivariate Cox regression analysis showed that high Notch1 expression was an independent favorable prognostic factor for SCLC(hazard ratio = 0.503, P = 0.023). High Notch1 expression, but not Numb expression, is associated with favorable prognosis in SCLC.

Highlights

Lung cancer is the leading cause of cancer-related death worldwide, and small cell lung cancer (SCLC) accounts for approximately 13–15% of new lung cancers each year [1]
Normal bronchial epithelial cells were used as positive controls of both Notch1 and Numb expression in immunohistochemical analyses
We demonstrated that Notch1 expression was associated with Eastern Cooperative Oncology Group performance status (ECOG PS) and that Numb expression was associated with age, sex, and pathological histology

Summary

Introduction

Lung cancer is the leading cause of cancer-related death worldwide, and small cell lung cancer (SCLC) accounts for approximately 13–15% of new lung cancers each year [1]. The Notch signaling pathway regulates many fundamental processes essential for normal development such as the control of cell differentiation, survival, proliferation, and angiogenesis. There are four Notch receptors (Notch to Notch4) and two families of ligands, Jagged (JAG1, 2) and Delta-like ligands (DLL1, 3, 4). Binding of Notch ligands induces proteolytic cleavage of Notch receptor by γ-secretase, thereby releasing the Notch intracellular domain (NICD) into the cytoplasm. The NICD enters the nucleus, interacts with the transcription factor CBF1/Suppressor of Hairless/Lag (CSL), and induces the transcription of several target genes, including hairy enhancer of split 1 (HES1) [3, 4]

Methods

Results

Conclusion