Abstract
B-Myb is an important transcription factor that plays a critical role in gene expression regulation and tumorigenesis. However, its functional implication in colorectal cancer remains elusive. In this study, we found that B-Myb was significantly upregulated at both mRNA and protein levels in colorectal cancer samples compared to non-tumor counterparts. B-Myb overexpression accelerated cell proliferation, cell cycle progression and cell motility in colorectal cancer cells, and promoted tumor growth in orthotopic nude mouse models in vivo. In contrast, B-Myb depletion inhibited these malignant phenotypes. Mechanistic investigations revealed that E2F2 was a novel transcriptional target of B-Myb and is essential to B-Myb-induced malignant phenotypes. Notably, B-Myb and E2F2 exhibited positive expression correlation, and interacted with each other in colorectal cancer cells. In addition to their autoregulatory mechanisms, B-Myb and E2F2 can also directly transactivate each other, thus constituting consolidated reciprocal feed-forward transactivation loops. Moreover, both B-Myb and E2F2 are required for the activation of ERK and AKT signaling pathways in colorectal cancer cells. Taken together, our data clarified a critical role for B-Myb in colorectal cancer and unraveled an exquisite mutual collaboration and reciprocal cross regulation between B-Myb and E2F2 that contribute to the malignant progression of human colorectal cancer.
Highlights
The colorectal cancer (CRC) is one of the most common cancers and the main cause of cancer-related deaths worldwide [1]
Upregulation of B-Myb is associated with the progression of human colorectal cancer To examine the expression of B-Myb in human CRC, we first downloaded the B-Myb expression data of colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ) from the Cancer Genome Atlas
Further quantitative RT-PCR analysis on human CRC cDNA array (Supplementary Table S1) verified that B-Myb mRNA was remarkably elevated in CRC samples compared with normal colorectal tissues (p < 0.01), and of note, the expression level of B-Myb mRNA was positively correlated with pathologic grade (p < 0.05, Fig. 1c)
Summary
The colorectal cancer (CRC) is one of the most common cancers and the main cause of cancer-related deaths worldwide [1]. The dissemination of colonoscopy with polypectomy has led to a decline in the incidence and mortality rates, CRC is still the second most prevalent cancers among males and the third among females. For the patients diagnosed with stage I or II, 5-year relative survival rates are 91% and 82%, respectively. 5-year survival declines to 12% for stage IV disease [2]. The combination of surgical therapy and chemotherapy is one of the leading means to treat the colorectal tumors. The prognosis of patients with CRC remains relatively poor, with a recurrent rate over 30% after curative surgery [3, 4].
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