FOXM1 promotes invasion and migration of colorectal cancer cells partially dependent on HSPA5 transactivation.

Xiaoyong Luo,Hongbo Feng,Pinjia Chen,Jinke Yao,Xinpeng Shi,Zhengzhi Zou,Peipei Nie,Zhiyuan Yang

doi:10.18632/oncotarget.8419

Abstract

In this study, to investigate whether endoplastic reticulum (ER) stress correlated with FOXM1 in colorectal cancer, we analysed the mRNA levels of FOXM1 and ER stress markers HSPA5 and spliced XBP1 by qRT-PCR. FOXM1 mRNA levels were found to positively correlate with HSPA5 in colorectal cancer. However, no significant correlation between FOXM1 and spliced XBP1 mRNA levels was found. Theses results suggested the positive correlation between FOXM1 and HSPA5 in colorectal cancer was not associated with ER stress. Next, we provided evidences that FOXM1 promoted HSPA5 transcription by directly binding to and stimulating HSPA5 promoter. Moreover, a FOXM1-binding site mapped between -1019 and -1012 bp of the proximal HSPA5 promoter was identified. In addition, we found that enhancement of cell migration and invasion by FOXM1 was significantly attenuated by depletion of HSPA5 in colorectal cancer cell. Furthermore, FOXM1 triggered colorectal cancer cell migration and invasion was involved in activities of cell-surface HSPA5. Lastly, our results suggested FOXM1 facilitated the activities and expressions of MMP2 and 9 associated with cell-surface HSPA5 in colorectal cancer cells. Moreover, statistically significant positive correlations between FOXM1 and MMP2 mRNA expression, between HSPA5 and MMP2 were found in colorectal cancer tissue specimens. Together, our results suggested that FOXM1-HSPA5 signaling might be considered as a novel molecular target for designing novel therapeutic regimen to control colorectal cancer metastasis and progression.

Highlights

Colorectal cancer is one of the most commonly occurring tumors and a prevalent cause of cancer-related death worldwide [1]
FOXM1 mRNA expression is elevated in most colorectal cancer tissues and positively correlated with heat shock kDa protein 5 (HSPA5)
Western blot analysis revealed that protein levels of FOXM1 and HSPA5 were upregulated in tumor samples relative to normal tissues (Figure 1E)

Summary

Introduction

Colorectal cancer is one of the most commonly occurring tumors and a prevalent cause of cancer-related death worldwide [1]. Previous reports show FOXM1 promotes tumorigenesis and is widely overexpressed in a multitude of human solid tumors, including colorectal cancer [4,5,6]. Increasing evidence has indicated that FOXM1 plays an important role in the metastasis of several malignances including colorectal, pancreatic, ovarian and breast cancer [5, 6, 11, 12]. Studies have shown that enhanced FOXM1 levels promote cancer cell invasion and metastasis by inducing epithelialto-mesenchymal transition (EMT) [12]. FOXM1 has been found to increase colorectal cancer migration and invasion by regulating a various signal pathways, such as urokinase-type plasminogen activator receptor (uPAR) and matrix metalloproteinase 2 and 9 (MMP2 and 9) signaling pathway [13]

Methods

Results

Conclusion