Notch Signaling Target Genes are Directly Correlated to Esophageal Squamous Cell Carcinoma Tumorigenesis

Abstract

Notch signaling is an important cellular pathway which affects the development and function of many organs. It plays critical roles in maintaining of progenitor stem cell population as well as balancing cell proliferation, survival, differentiation and apoptosis. It has been shown that notch signaling is aberrantly activated during the carcinogenesis of a variety of human cancers. In this study we aimed to explore activation of this signaling pathway in esophageal squamous cell carcinoma (ESCC) through expressional analysis of notch signaling target genes. The mRNA expression of HEY1 and HEY2 was comparatively analyzed by real-time PCR in tumor and related margin normal tissues of 50 ESCC patients. Comparative quantitative real-time PCR indicates the overexpression of HEY1 and HEY2 in 54 and 30% of ESCC samples, respectively. Overexpression of HEY1 was significantly associated with stage of the tumor (p = 0.048) and tumor location (p = 0.008). HEY2 overexpression was also significantly correlated to node metastasis of tumor cells (p = 0.043). Overexpression of HEY1 and HEY2 in ESCC is correlated to different indices of poor prognosis and it is extrapolated that such overexpression is important in progression and development of ESCC tumorigenesis. To the best of our knowledge, this is the first report introducing aberrant activation of notch signaling target genes in ESCC, where it plays roles in development and progression of the malignancy and may be considered in therapeutic modalities to restrict ESCC progression.

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

“…This concept may need to be further validated with the studies targeting SCCs from other tissues, such as lung and cervical whose molecular pathogenesis remains poorly understood. However, the oncogenic role of Notch in HNSCC is likely, as the increased levels of Notch signaling components in OSCC/ESCC were reported 82, 84, 85, although their biological consequences remain to be determined.…”

“…The main concern is regarding the elevated levels of Notch signaling pathway genes in different HNSCC/ESCC. Notch signaling pathway components (including Notch receptors, ligands, or targets genes such as HES1 , HEY1 , or HEY2 ) were found to be amplified or overexpressed in a subset of tongue tumor samples 80, in HNSCC tumors over normal mucosa 81, in OSCC 82, 83, 84, and frequently in ESCC samples 85.…”

Novel candidate genes may be possible predisposing factors revealed by whole exome sequencing in familial esophageal squamous cell carcinoma

“…Aberrant activation of Notch signaling has been revealed during the carcinogenesis of a variety of human cancers. 9,10 Clinical trials of Notch signaling pathway inhibitors have been reported in patients with solid tumors, including breast cancer and T-cell acute lymphoblastic leukemia (T-ALL), 10 and preclinical evaluation of several approaches is under consideration. 11 However, the roles of the Notch signaling pathway in esophageal tumor biology remain elusive.…”

Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

“…In these malignant carcinomas, aberrant Hey expression has been associated with poor prognosis, overall survival (OS), tumor grade, chemotherapy resistance, lymphatic metastasis, and vascular proliferative properties (17,(23)(24)(25). Taken together, these studies suggest that elevated levels of Hey proteins contribute to tumor progression, and to a certain extent, this is a result of their regulation of the behavior of cancer cells as well as remodeling of the tumor microenvironment (Fig.…”

“…The levels of Hey factors are strikingly elevated in high-grade glioma, malignant osteosarcoma, high-grade esophageal squamous cell carcinoma, aggressive pancreatic adenocarcinoma rhabdomyosarcoma, as well as colorectal carcinoma (17)(18)(19)(20)(21)(22)(23). In these malignant carcinomas, aberrant Hey expression has been associated with poor prognosis, overall survival (OS), tumor grade, chemotherapy resistance, lymphatic metastasis, and vascular proliferative properties (17,(23)(24)(25).…”