Research Papers:

FoxO3a confers cetuximab resistance in RAS wild-type metastatic colorectal cancer through c-Myc

Yiyi Yu, Mengzhou Guo, Ye Wei, Shan Yu, Hong Li, Yan Wang, Xiaojing Xu, Yuehong Cui, Jiawen Tian, Li Liang, Ke Peng and Tianshu Liu _

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Oncotarget. 2016; 7:80888-80900. https://doi.org/10.18632/oncotarget.13105

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Yiyi Yu1,*, Mengzhou Guo1,*, Ye Wei2,*, Shan Yu1, Hong Li1, Yan Wang1, Xiaojing Xu1, Yuehong Cui1, Jiawen Tian1, Li Liang1, Ke Peng1, Tianshu Liu1

1Department of Medical Oncology, Zhong Shan Hospital, Fu Dan University, Shanghai, China

2Department of General Surgery, Zhong Shan Hospital, Fu Dan University, Shanghai, China

*These authors contributed equally to this work

Correspondence to:

Tianshu Liu, email: [email protected]

Keywords: cetuximab resistance, FoxO3a, c-Myc, RAS, colorectal cancer

Received: May 31, 2016     Accepted: October 14, 2016     Published: November 04, 2016


Resistance to epidermal growth factor receptor (EGFR) targeted monoclonal antibody therapy represents a clinical challenge in patients suffered from RAS wild-type (WT) metastatic colorectal cancer (mCRC). However, the molecular mechanisms and key factors conferring this resistance are largely unknown. Forkhead transcription factors of the O class 3a (FoxO3a), an important regulator of cell survival, has been reported with dual functions in tumor recently. In this study, we found that FoxO3a was highly expressed in cetuximab resistant CRC tissues compared with cetuximab sensitive tissues. We therefore further analyzed its function in induced cetuximab resistant RAS-WT CRC cells (Caco2-CR) and intrinsic resistant cells with BRAF mutation (HT29). We found that FoxO3a was significantly up-regulated in Caco2-CR as well as in cetuximab treated HT29 cells. Knockdown of FoxO3a could sensitize these cells to cetuximab treatment with reduced cell proliferation and migration ability. Further, biochemical experiments demonstrated that FoxO3a directly bind to c-Myc promoter and activated the transcription of the c-Myc gene, thus participated in regulating of c-Myc downstream genes, including ACO2, LARS2, MRPL12 and PKM2 in these resistant cells. Moreover, knockdown of c-Myc elevated cell apoptosis to cetuximab treatment and suppressed cell proliferation and migration ability consistently. Altogether, our study indicates that FoxO3a might be a key regulator in cetuximab resistance through up-regulating c-Myc in colorectal cancer targeted therapy.

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