Jab1 promotes gastric cancer tumorigenesis via non-ubiquitin proteasomal degradation of p14ARF
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ORIGINAL ARTICLE
Jab1 promotes gastric cancer tumorigenesis via non‑ubiquitin proteasomal degradation of p14ARF Lin Wang1,2 · Wen‑Qi Du1,3 · Min Xie1 · Man‑Ru Liu1 · Fu‑Chun Huo1 · Jing Yang4 · Dong‑Sheng Pei1 Received: 3 April 2020 / Accepted: 16 May 2020 © The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2020
Abstract Background Jab1 has been reported to regulate various proteins in signal transduction pathways and be implicated in carcinogenesis or tumor progression. However, the precise role and molecular mechanism of Jab1 in gastric tumorigenesis have not yet been fully elucidated. Methods Jab1 staining in gastric cancer tissues and paired non-cancerous tissues was measured using tissue microarray (TMA) technology. The impact of Jab1 on tumor growth in vivo was analyzed using xenotransplantation experiments in Balb/c mice. The expression of Jab1 and p14ARF in gastric cancer cells was analyzed by western blot and confocal immunofluorescence. CCK-8 and cell cycle experiment were used to evaluate the cell proliferation. Ubiquitination assay was performed to validate whether ubiquitination is involved in Jab1-mediated p14ARF degradation. Results The expression level of protein p14ARF was inversely correlated with the protein level of Jab1. Then, we investigated the mechanism that how Jab1 induced p14ARF depletion. Mechanistic studies showed that Jab1 induced ubiquitinindependent proteasomal p14ARF degradation in gastric cancer cells. Our data demonstrated that Jab1 protein was a vital upstream negative modulation factor of p14ARF, and Jab1 could promote cell proliferation and tumor growth via inhibiting the expression of p14ARF in vivo and in vitro. Moreover, silencing Jab1 protein expression declined tumor growth and further increased the apoptosis rate of gastric cancer cells. In further studies of gastric cancer specimens, we found the increased level of Jab1 protein shortened the overall survival. Conclusion Jab1 is upstream of p14ARF and promote gastric cancer cell proliferation in vitro and in vivo. Furthermore, Jab1 decreased the expression of p14ARF though ubiquitination independent proteasomal degradation. Therefore, the connection of Jab1 and p14ARF may provide new methods for the treatment of gastric cancer. Keywords Jab1 · p14ARF · Cell proliferation · Apoptosis · Gastric cancer Lin Wang and Wen-Qi Du contributed equally to this paper. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10120-020-01087-z) contains supplementary material, which is available to authorized users. * Dong‑Sheng Pei [email protected] 1
Department of Pathology, Xuzhou Medical University, 209 Tong‑shan Road, Xuzhou 221004, Jiangsu, China
2
Department of Respiratory Medicine, Second Affiliated Hospital of Xuzhou Medical University, Xuzhou 221004, China
3
Department of Human Anatomy, Xuzhou Medical University, Xuzhou 221004, China
4
Department of Oncology, Xuzhou Hospital Affiliated to Nanjing University of Chinese Medicin
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