IFN‐α/β‐mediated NK2R expression is related to the malignancy of colon cancer cells

• Published in: Cancer science Vol. 113; no. 8; pp. 2513 - 2525
• Main Authors: Xiang, Huihui, Toyoshima, Yujiro, Shen, Weidong, Wang, Xiangdong, Okada, Naoki, Kii, Shuhei, Sugiyama, Ko, Nagato, Toshihiro, Kobayashi, Hiroya, Ikeo, Kazuho, Hashimoto, Shinichi, Tanino, Mishie, Taketomi, Akinobu, Kitamura, Hidemitsu
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01-08-2022; John Wiley and Sons Inc
• Subjects: Apoptosis; Biotechnology; Blood vessels; Cell cycle; Cell growth; Cell proliferation; Colon cancer; Colorectal cancer; Colorectal carcinoma; CRISPR; Dendritic cells; Experiments; Extracellular signal-regulated kinase; Flow cytometry; Gene expression; Inoculation; Interferon; Irritable bowel syndrome; JAK; Kinases; Laboratory animals; Malignancy; Metastases; Metastasis; Muscle contraction; Neurokinin; Neurokinin A; Neurokinin NK2 receptors; neurokinin‐2 receptor; Neuropeptides; Original; ORIGINAL ARTICLES; Patients; Permeability; Phosphorylation; Smooth muscle; Tachykinin; Tachykinin receptors; Tumorigenesis; type I IFN; neurokinin-2 receptor; malignancy; type I IFN; JAK; colon cancer
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15397

Neurokinin 2 receptor (NK2R), a G protein‐coupled receptor for neurokinin A (NKA), a tachykinin family member, regulates various physiological functions including pain response, relaxation of smooth muscle, dilation of blood vessels, and vascular permeability. However, the precise role and regulation of NK2R expression in cancer cells have not been fully elucidated. In this study, we found that high NK2R gene expression was correlated with the poor survival of colorectal cancer patients, and Interferon (IFN‐α/β) stimulation significantly enhanced NK2R gene expression level of colon cancer cells in a Janus kinas 1/2 (JAK 1/2)‐dependent manner. NKA stimulation augmented viability/proliferation and phosphorylation of Extracellular‐signal‐regulated kinase 1/2 (ERK1/2) levels of IFN‐α/β‐treated colon cancer cells and NK2R blockade by using a selective antagonist reduced the proliferation in vitro. Administration of an NK2R antagonist alone or combined with polyinosinic‐polycytidylic acid, a synthetic analog of double‐stranded RNA, to CT26‐bearing mice significantly suppressed tumorigenesis. NK2R‐overexpressing CT26 cells showed enhanced tumorigenesis and metastatic colonization in both lung and liver after the inoculation into mice. These findings indicate that IFN‐α/β‐mediated NK2R expression is related to the malignancy of colon cancer cells, suggesting that NK2R blockade may be a promising strategy for colon cancers.
IFN‐α/β induced neurokinin 2 receptor (NK2R), a G protein‐coupled receptor for neurokinin A in a JAK1/2‐dependent manner. NK2R expression was related to the tumorigeneis and mietastatic colonization of colon cancer cells. Therefore, NK2R blockade will be a promising strategy for colon cancers.