Int J Biol Sci 2019; 15(5):1080-1090. doi:10.7150/ijbs.31484

Research Paper

ASB6 Promotes the Stemness Properties and Sustains Metastatic Potential of Oral Squamous Cell Carcinoma Cells by Attenuating ER Stress

Kai-Feng Hung1,2,4, Po-Chen Liao3, Chih-Kai Chen3, Yueh-Ting Chiu3, Dong-Hui Cheng4, Masaoki Kawasumi5, Shou-Yen Kao2,4✉, Jeng-Fan Lo2,3,6,7,8✉

1. Department of Medical Research, Division of Translational Research, Taipei Veterans General Hospital, Taipei, Taiwan
2. Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei, Taiwan
3. Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan
4. Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan
5. Division of Dermatology, Department of Medicine, University of Washington, Seattle, Washington 98109, USA.
6. Graduate Institute of Chinese Medical Science and Institute of Medical Science, China Medical University, Taichung, Taiwan
7. Genome Research Center, National Yang-Ming University, Taipei, Taiwan
8. Cancer Progression Center of Excellence, National Yang-Ming University, Taipei, Taiwan

Abstract

Up-regulation of ASB6 has been previously associated with late-stage and poor prognosis of oral squamous cell carcinoma (OSCC) patients. To explore the cellular and molecular basis of how ASB6 enhances the malignancy of OSCC, we employed the clonogenicity and migration assays, murine pulmonary metastasis model, Western blot, and immunofluorescence microscopy to characterize the phenotypes of OSCC cells with lentiviral-based stable overexpression or knockdown of ASB6. We found that ASB6 overexpression increases, whereas ASB6 knockdown decreases, the potential of tumor-sphere formation, colony formation, and expression of Oct-4 and Nanog. While knockdown of ASB6 decreases cell migration in vitro and lung metastasis in mice, the migratory potential was however not promoted by ASB6 overexpression. ASB6 knockdown down-regulates the level of vimentin, and the loss of filopodia formation became more prominent following CRISPR/Cas9-directed knockout of ASB6. Moreover, ASB6 was up-regulated when cells were grown in selective condition featured with a collateral effect of enhancing intracellular stress, and the level of endoplasmic reticulum (ER) stress was further increased by knockdown of ASB6. Thus, ASB6 may attenuate ER stress that would otherwise accumulate and subsequently impede the potential of cells to acquire or sustain the stemness properties and metastatic capacity, thereby enhancing the malignancy of OSCC by increasing the population of cancer stem or stem-like cells.

Keywords: ASB6, stemness, metastasis, endoplasmic reticulum (ER) stress, oral squamous cell carcinoma (OSCC)

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
How to cite this article:
Hung KF, Liao PC, Chen CK, Chiu YT, Cheng DH, Kawasumi M, Kao SY, Lo JF. ASB6 Promotes the Stemness Properties and Sustains Metastatic Potential of Oral Squamous Cell Carcinoma Cells by Attenuating ER Stress. Int J Biol Sci 2019; 15(5):1080-1090. doi:10.7150/ijbs.31484. Available from http://www.ijbs.com/v15p1080.htm