Ninjurin1 suppresses metastatic property of lung cancer cells through inhibition of interleukin 6 signaling pathway

• Published in: International journal of cancer 2016-07, Vol.139 (2), p.383-395
• Main Authors: Jang, Yeong‐Su, Kang, Ju‐Hee, Woo, Jong Kyu, Kim, Hwan Mook, Hwang, Jong‐Ik, Lee, Sang‐Jin, Lee, Ho‐Young, Oh, Seung Hyun
• Format: Article
• Language: English
• Subjects: Adhesion; Axonogenesis; Cancer; Cell adhesion; Cell adhesion & migration; Cell Adhesion Molecules, Neuronal - metabolism; Cell Line, Tumor; Cell migration; Cell Movement - genetics; Cell surface; Cytokines; Dorsal root ganglia; Gene Expression; Humans; Incidence; Inhibition; Intercellular adhesion molecule 1; Intercellular Adhesion Molecule-1 - genetics; Intercellular Adhesion Molecule-1 - metabolism; Interleukin 6; Interleukin-6 - genetics; Interleukin-6 - metabolism; Invasiveness; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lungs; Medical research; Metastases; Metastasis; Migration; Neoplasm Metastasis; Nerve Growth Factors - metabolism; nerve injury‐induced protein 1; Neurons; Nodules; RNA, Small Interfering - genetics; Secretion; Signal Transduction; Stat3 protein; STAT3 Transcription Factor - metabolism; Therapeutic applications
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.30021

Nerve injury‐induced protein 1 (Ninjurin1, Ninj1) is a cell surface molecule that can mediate homophilic adhesion and promote neurite outgrowth from cultured dorsal root ganglion (DRG) neurons. Interestingly, Ninj1 overexpressed in human cancer; however, its role in metastasis is not clear. This study showed that inhibition of Ninj1 promotes lung cancer metastasis through interleukin 6 (IL‐6)/STAT3 signaling. Ninj1 levels were relatively low in highly motile lung cancer cells. While inhibition of Ninj1 enhanced cell migration in lung cancer cells, overexpression of Ninj1 significantly suppressed it. We found that inhibition of Ninj1 significantly increased expression and secretion of IL‐6 in A549 cells. We also found that inhibition of IL‐6 decreased intercellular adhesion molecule 1 (ICAM‐1) expression. In addition, inhibition of Ninj1 significantly increased cell motility and invasiveness of lung cancer cells. In an in vivo model, we found that Ninj1 suppression did not affect tumor growth but induced significant increase in incidence of lung metastasis, and sizes and number of tumor nodules. Taken together, our data clearly demonstrate that Ninj1 suppresses migration, invasion and metastasis of lung cancer via inhibition of the IL‐6 signaling pathway in vitro and in vivo. What's new? The cell‐adhesion molecule Ninj1 is overexpressed in human cancers, but its role in metastasis has been unclear. In this study of an in vivo model of lung cancer, the authors found that Ninj1 acts as a “metastasis suppressor gene” in human lung‐cancer cells. When Ninj1 was blocked, cancer cell migration, invasion, and metastasis increased. Conversely, overexpression of Ninj1 reduced metastasis, and this was due to inhibition of the IL‐6/STAT3 signaling pathway. Further study of Ninj1 might, therefore, lead to useful therapeutic applications in cancer treatment.