BMAL1 promotes colorectal cancer cell migration and invasion through ERK- and JNK-dependent c-Myc expression

Lina Shan; Wenqian Zheng; Bingjun Bai; Jinghui Hu; Yiming Lv; Kangke Chen; Xiaowei Wang; Yangtao Pan; Xuefeng Huang; Hongbo Zhu; Sheng Dai

doi:10.1002/cam4.5129

BMAL1 promotes colorectal cancer cell migration and invasion through ERK- and JNK-dependent c-Myc expression

Cancer Med. 2023 Feb;12(4):4472-4485. doi: 10.1002/cam4.5129. Epub 2022 Aug 10.

Authors

Lina Shan^{1

2}, Wenqian Zheng^{1

2}, Bingjun Bai^{1

2}, Jinghui Hu^{1

2}, Yiming Lv^{1

2}, Kangke Chen², Xiaowei Wang^{1

2}, Yangtao Pan^{1

2}, Xuefeng Huang¹, Hongbo Zhu^{1

2}, Sheng Dai^{1

2}

Affiliations

¹ Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
² Key Laboratory of Biotherapy of Zhejiang province, Hangzhou, China.

Abstract

Background: Cancer metastasis is still a life threat to patients with colorectal cancer (CRC). Brain and muscle ARNT-like protein 1 (BMAL1) is an important biological proteins that can regulate the behavior of cancer cells and their response to chemotherapy. However, the role of BMAL1 in the tumorigenic phenotype of CRC remains unclear. Here, we aim to investigate the functional role and mechanisms of BMAL1 in CRC.

Methods: The mRNA expression of BMAL1 was studied using the Cancer Genome Atlas (TCGA) databases. The protein level in clinical tissues was confirmed by immunohistochemistry (IHC). The effects of BMAL1 on the epithelial-to-mesenchymal transition (EMT) and proliferation of CRC cell lines (including BMAL1 overexpressed or silencing cells) were studied by Transwell, wound healing, CCK-8 and colony formation experiments. A series of experiments were conducted to demonstrate the mechanisms of BMAL1 regulating EMT and cancer proliferation in vitro and in vivo.

Results: We found that BMAL1 expression was closely related to the poor prognosis of CRC. BMAL1 overexpression promoted cell proliferation and migration. Mechanistically, we found that BMAL1 may activate the epithelial-to-mesenchymal transition (EMT) pathway and induce the β-catenin release further promotes the expression of oncogene c-Myc and the migration of colorectal cells by activating MAPK pathway. However, BMAL1 silencing achieved the opposite effect. In addition, blocking MAPK-signaling pathway with specific inhibitors of ERK1/2 and JNK can also downregulate the expressions of c-Myc in vitro. Taken together, these results suggested that the BMAL1/ c-Myc-signaling pathway may regulate the metastasis of CRC through the JNK/ERK1/2 MAPK-dependent pathway.

Conclusions: Our study showed that BMAL1 promotes CRC metastasis through MAPK-c-Myc pathway. These results deepen our understanding of the relationship between BMAL1 and tumorigenic phenotypes, which may become a promising therapeutic target for BMAL1 overexpressing CRC.

Keywords: BMAL1; EMT; MAPK signaling pathway; c-Myc; colorectal cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ARNTL Transcription Factors* / genetics
Cell Line, Tumor
Cell Movement / genetics
Cell Proliferation
Colorectal Neoplasms* / pathology
Epithelial-Mesenchymal Transition / genetics
Extracellular Signal-Regulated MAP Kinases / metabolism
Gene Expression Regulation, Neoplastic
Humans
MAP Kinase Kinase 4 / metabolism
Proto-Oncogene Proteins c-myc / metabolism
Signal Transduction

Substances

ARNTL Transcription Factors
Proto-Oncogene Proteins c-myc
MAP Kinase Kinase 4
Extracellular Signal-Regulated MAP Kinases