JAG1 Is Associated with Poor Survival through Inducing Metastasis in Lung Cancer

Wen-Hsin Chang; Bing-Ching Ho; Yi-Jing Hsiao; Jin-Shing Chen; Chien-Hung Yeh; Hsuan-Yu Chen; Gee-Chen Chang; Kang-Yi Su; Sung-Liang Yu

doi:10.1371/journal.pone.0150355

JAG1 Is Associated with Poor Survival through Inducing Metastasis in Lung Cancer

PLoS One. 2016 Mar 1;11(3):e0150355. doi: 10.1371/journal.pone.0150355. eCollection 2016.

Authors

Wen-Hsin Chang¹, Bing-Ching Ho², Yi-Jing Hsiao², Jin-Shing Chen^{3

4}, Chien-Hung Yeh², Hsuan-Yu Chen⁵, Gee-Chen Chang^{6

7}, Kang-Yi Su^{2

8}, Sung-Liang Yu^{2

8

9

10

11

12}

Affiliations

¹ Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
² Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
³ Division of Thoracic Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
⁴ Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
⁵ Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
⁶ Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
⁷ Comprehensive Cancer Center, Taichung Veterans General Hospital, Taichung, Taiwan.
⁸ Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.
⁹ Department of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan.
¹⁰ Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan.
¹¹ Center for Optoelectronic Biomedicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
¹² Institute of Medical Device and Imaging, College of Medicine, National Taiwan University, Taipei, Taiwan.

Abstract

JAG1 is a Notch ligand that plays a critical role in multiple signaling pathways. However, the functionality of JAG1 in non-small cell lung cancer (NSCLC) has not been investigated thoroughly. By comparison of gene transcripted RNA profiles in the cell line pair with differential invasion ability, we identified JAG1 as a potential metastasis enhancer in lung cancer. Ectopic expression of JAG1 on lung cancer cells enhanced cell migration and invasion as well as metastasis in vitro and in vivo. Conversely, knockdown of JAG1 with siRNA in highly invasive cancer cells led to the reduction of migration and invasion. In clinical analysis, JAG1 mRNA expression was higher in tumors than in adjacent normal tissues in 14 of 20 patients with squamous cell carcinoma (SCC). SCC patients with higher JAG1 transcription had poor overall survival than those with low-transcripted JAG1. Microarray analysis indicated that the enforced JAG1 transcription was associated with an elevated HSPA2 RNA transcription, which played a role in promoting cancer cell migration and invasion. In conclusion, this is the first study that demonstrated that JAG1 might act as a potential prognostic marker and JAG1/HSPA2 axis mediates lung cancer malignancy at least partly.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biomarkers, Tumor / genetics
Calcium-Binding Proteins / genetics*
Carcinoma, Non-Small-Cell Lung / genetics
Carcinoma, Non-Small-Cell Lung / pathology
Carcinoma, Squamous Cell / genetics
Carcinoma, Squamous Cell / pathology
Cell Line, Tumor
Cell Movement / genetics
HSP70 Heat-Shock Proteins / genetics
Humans
Intercellular Signaling Peptides and Proteins / genetics*
Jagged-1 Protein
Lung Neoplasms / genetics*
Lung Neoplasms / pathology*
Membrane Proteins / genetics*
Mice
Mice, SCID
Neoplasm Invasiveness / genetics
Neoplasm Invasiveness / pathology
Neoplasm Metastasis / genetics*
Neoplasm Metastasis / pathology
Prognosis
Serrate-Jagged Proteins

Substances

Biomarkers, Tumor
Calcium-Binding Proteins
HSP70 Heat-Shock Proteins
HSPA2 protein, human
Intercellular Signaling Peptides and Proteins
JAG1 protein, human
Jag1 protein, mouse
Jagged-1 Protein
Membrane Proteins
Serrate-Jagged Proteins

Grants and funding

This study was supported by the grants from the Ministry of Science and Technology, Taiwan, R.O.C. (NSC98-2314-B-002-038-MY2, NSC101-2911-I-002-303, 103-2320-B-002 -052, 104-2320-B-002 -030). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.