Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 21, 2019; 25(15): 1840-1853
Published online Apr 21, 2019. doi: 10.3748/wjg.v25.i15.1840
Predictive and prognostic implications of 4E-BP1, Beclin-1, and LC3 for cetuximab treatment combined with chemotherapy in advanced colorectal cancer with wild-type KRAS: Analysis from real-world data
Gui-Fang Guo, Yi-Xing Wang, Yi-Jun Zhang, Xiu-Xing Chen, Jia-Bin Lu, Hao-Hua Wang, Chang Jiang, Hui-Quan Qiu, Liang-Ping Xia
Gui-Fang Guo, Yi-Xing Wang, Xiu-Xing Chen, Hao-Hua Wang, Chang Jiang, Hui-Quan Qiu, Liang-Ping Xia, VIP Department, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong Province, China
Gui-Fang Guo, Yi-Xing Wang, Yi-Jun Zhang, Xiu-Xing Chen, Jia-Bin Lu, Hao-Hua Wang, Chang Jiang, Hui-Quan Qiu, Liang-Ping Xia, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong Province, China
Gui-Fang Guo, Yi-Xing Wang, Yi-Jun Zhang, Xiu-Xing Chen, Jia-Bin Lu, Hao-Hua Wang, Chang Jiang, Hui-Quan Qiu, Liang-Ping Xia, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, Guangdong Province, China
Yi-Jun Zhang, Jia-Bin Lu, Pathology Department, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong Province, China
Author contributions: Guo GF designed the research; Guo GF and Wang YX analyzed the data and wrote the paper; Chen XX and Wang HH performed the experiments; Zhang YJ and Lu JB contributed new reagents and analytic tools; Jiang C and Qiu HQ collected the data; Xia LP amended the paper; all of the authors have read and approved the final manuscript.
Institutional review board statement: This study was approved by the Ethics Committee of the Sun Yat-sen University Cancer Center, Guangdong, China. All patients involved in this study gave their informed consent for participation in the study.
Conflict-of-interest statement: The authors have no conflict of interest relevant to this study.
Data sharing statement: The manuscript has no additional data available.
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: Gui-Fang Guo, MD, PhD, Professor, VIP Department, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, Guangdong Province, China. guogf@sysucc.org.cn
Telephone: +86-20-87342708 Fax: +86-20-87342708
Received: January 24, 2019
Peer-review started: January 24, 2019
First decision: February 26, 2019
Revised: March 20, 2019
Accepted: March 24, 2019
Article in press: March 25 2019
Published online: April 21, 2019
Processing time: 84 Days and 16.7 Hours
Abstract
BACKGROUND

Colorectal cancer (CRC) is one of the main causes of cancer-related deaths in China and around the world. Advanced CRC (ACRC) patients suffer from a low cure rate though treated with targeted therapies. The response rate is about 50% to chemotherapy and cetuximab, a monoclonal antibody targeting epidermal growth factor receptor (EGFR) and used for ACRC with wild-type KRAS. It is important to identify more predictors of cetuximab efficacy to further improve precise treatment. Autophagy, showing a key role in the cancer progression, is influenced by the EGFR pathway. Whether autophagy can predict cetuximab efficacy in ACRC is an interesting topic.

AIM

To investigate the effect of autophagy on the efficacy of cetuximab in colon cancer cells and ACRC patients with wild-type KRAS.

METHODS

ACRC patients treated with cetuximab plus chemotherapy, with detailed data and tumor tissue, at Sun Yat-sen University Cancer Center from January 1, 2005, to October 1, 2015, were studied. Expression of autophagy-related proteins [Beclin1, microtubule-associated protein 1A/B-light chain 3 (LC3), and 4E-binding protein 1 (4E-BP1)] was examined by Western blot in CRC cells and by immunohistochemistry in cancerous and normal tissues. The effect of autophagy on cetuximab-treated cancer cells was confirmed by MTT assay. The associations between Beclin1, LC3, and 4E-BP1 expression in tumor tissue and the efficacy of cetuximab-based therapy were analyzed.

RESULTS

In CACO-2 cells exposed to cetuximab, LC3 and 4E-BP1 were upregulated, and P62 was downregulated. Autophagosome formation was observed, and autophagy increased the efficacy of cetuximab. In 68 ACRC patients, immunohistochemistry showed that Beclin1 levels were significantly correlated with those of LC3 (0.657, P < 0.001) and 4E-BP1 (0.211, P = 0.042) in ACRC tissues. LC3 was significantly overexpressed in tumor tissues compared to normal tissues (P < 0.001). In 45 patients with wild-type KRAS, the expression levels of these three proteins were not related to progression-free survival; however, the expression levels of Beclin1 (P = 0.010) and 4E-BP1 (P = 0.005), pathological grade (P = 0.002), and T stage (P = 0.004) were independent prognostic factors for overall survival (OS).

CONCLUSION

The effect of cetuximab on colon cancer cells might be improved by autophagy. LC3 is overexpressed in tumor tissues, and Beclin1 and 4E-BP1 could be significant predictors of OS in ACRC patients treated with cetuximab.

Keywords: 4E-binding protein 1; Beclin-1; Microtubule-associated protein 1A/B-light chain 3; Advanced colorectal cancer; Cetuximab efficacy; Prognosis

Core tip: Considering the response rate to cetuximab in advanced colorectal cancer patients with wild-type KRAS, autophagy might be a novel predictor to exclude patients who will not respond to cetuximab. Accordingly, Beclin1, microtubule-associated protein 1A/B-light chain 3 (LC3), and 4E-binding protein 1 (4E-BP1) were studied in this research. We found that LC3 was overexpressed in tumor tissues, and the expression levels of Beclin1 and 4E-BP1 were related to overall survival.