Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 7, 2019; 25(37): 5590-5603
Published online Oct 7, 2019. doi: 10.3748/wjg.v25.i37.5590
Oncogenic ADAM28 induces gemcitabine resistance and predicts a poor prognosis in pancreatic cancer
Li Wei, Jing-Yun Wen, Jie Chen, Xiao-Kun Ma, Dong-Hao Wu, Zhan-Hong Chen, Jiang-Long Huang
Li Wei, Jing-Yun Wen, Jie Chen, Xiao-Kun Ma, Dong-Hao Wu, Zhan-Hong Chen, Department of Medical Oncology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
Jiang-Long Huang, Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
Author contributions: Huang JL and Chen ZH conceived and directed the entire study, and should be regarded as co-corresponding authors; Wei L designed the study and prepared the manuscript; Wen JY defined the intellectual content of the study; Wei L and Wen JY contributed equally to this study; Wu DH and Chen J participated in the literature research and clinical study; Wu DH and Ma XK conducted the experiments and data analysis; Chen J provided the statistical analysis; Wen JY, Huang JL, and Chen ZH revised the manuscript. All authors approved to submit the manuscript.
Institutional review board statement: This study was approved by the Scientific Committee of the Third Affiliated Hospital of Sun Yat-Sen University.
Institutional animal care and use committee statement: This study was approved by the Ethical Committee of the Third Affiliated Hospital of Sun Yat-Sen University.
Conflict-of-interest statement: The authors declare no conflict of interest.
Data sharing statement: The bioinformatic data could be downloaded from the public databases, and no additional data are available.
ARRIVE guidelines statement: This study was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Jiang-Long Huang, MD, Associate Professor, Chief Doctor, Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600, Tianhe Road, Guangzhou 510630, Guangdong Province, China. drhjl@aliyun.com
Telephone: +86-20-85252228 Fax: +86-20-85252228
Received: July 30, 2019
Peer-review started: July 30, 2019
First decision: August 17, 2019
Revised: September 5, 2019
Accepted: September 9, 2019
Article in press: September 9, 2019
Published online: October 7, 2019
Processing time: 61 Days and 17.4 Hours
Abstract
BACKGROUND

Pancreatic cancer is a major cause of cancer-related death, with a 5-year overall survival rate being below 5%. The main causes of poor prognosis in pancreatic cancer include easy metastasis, high recurrence rate, and robust drug resistance. Gemcitabine is a first-line drug for patients with unresectable pancreatic cancer. However, due to drug resistance, the clinical effect is not satisfactory. ADAM28 is reported as a tumor promoter in some cancers, but its role in pancreatic cancer and gemcitabine chemoresistance in pancreatic cancer has not been elucidated.

AIM

To identify if ADAM28 can act as an important target to reverse the gemcitabine drug resistance in pancreatic cancer.

METHODS

RNA-sequence analysis was applied to explore the potential targets involved in the gemcitabine of pancreatic cancer. SW1990 pancreatic cancer cells were treated with an increased dose of gemcitabine, and the mRNA levels of ADAM28 were evaluated by RT-PCR. The protein and mRNA levels of ADAM28 were confirmed in the gemcitabine resistant and parallel SW1990 cells. The ADAM28 expression was also assessed in TCGA and GEO databases, and the results were confirmed in the collected tumor and adjacent normal tissues. The overall survival (OS) rate and relapse-free survival (RFS) rate of pancreatic cancer patients with high ADAM28 level and low ADAM28 level in TCGA were evaluated with Kaplan-Meier Plotter. Furthermore, the OS rate was calculated in pancreatic cancer patients with high tumor mutation burden (TMB) and low TMB. CCK-8 assay was used to examine the effect of ADAM28 on the viability of SW1990 cells. The ADAM28 and its co-expressed genes were analyzed in the cBioPortal for cancer genomics and subjected to GSEA pathway analysis. The correlations of ADAM28 with GSTP1, ABCC1, GSTM4, and BCL2 were analyzed based on TCGA data on pancreatic cancer.

RESULTS

RNA-sequence analysis identified that ADAM28 was overexpressed in gemcitabine-resistant cells, and gemcitabine treatment could induce the expression of ADAM28. The mRNA and protein levels of ADAM28 were elevated in gemcitabine-resistant SW1990 cells compared with parallel cells. Also, the expression of ADAM28 was upregulated in pancreatic tumor tissues against normal pancreatic tissues. Notably, ADAM28 was highly expressed in the classical type than in the basal tumor type. Furthermore, the high expression of ADAM28 was associated with low OS and RFS rates. Interestingly, the high levels of ADAM28 was associated with a significantly lower OS rate in the high TMB patients, but not in the low TMB patients. Moreover, overexpression of ADAM28 could reduce the cell viability inhibition by gemcitabine, and knockdown of ADAM28 could enhance the proliferation inhibition by gemcitabine. The GSEA analysis showed that ADAM28 was related to the regulation of drug metabolism, and ADAM28 was significantly positively correlated with GSTP1, ABCC1, GSTM4, and BCL2.

CONCLUSION

This study demonstrates that ADAM28 is overexpressed in pancreatic cancer, and closely involved in the regulation of gemcitabine resistance. Overexpression of ADAM28 is a novel prognostic biomarker in pancreatic cancer.

Keywords: ADAM28; Drug resistance; Overexpression; Poor prognosis; Drug metabolism; Gemcitabine

Core tip: This study demonstrated that ADAM28 was overexpressed in pancreatic cancer, and the ADAM28 level was elevated in gemcitabine-resistant pancreatic cancer cells. Furthermore, ADAM28 overexpression could predict a poor prognosis in pancreatic cancer. Also, overexpression of ADAM28 could attenuate the cell viability inhibition by gemcitabine, while knockdown of ADAM28 could enhance the cell viability inhibition by gemcitabine. Interestingly, ADAM28 was identified as a mediator which is closely involved in the regulation of drug resistance-related signaling pathways. ADAM28 was identified as a novel therapeutic target for pancreatic cancer, especially in case of resistance to gemcitabine.