IMPDH2 promotes colorectal cancer progression through activation of the PI3K/AKT/mTOR and PI3K/AKT/FOXO1 signaling pathways

Shiyu Duan,Jun Zhou,Wenqing Huang,Nana Chen,Yukun Hu,Qiong Xu,Xiaoting Liu,Xuming Liu,Wen Song

doi:10.1186/s13046-018-0980-3

Abstract

BackgroundInosine 5′-monophosphate dehydrogenase type II (IMPDH2) was originally identified as an oncogene in several human cancers. However, the clinical significance and biological role of IMPDH2 remain poorly understood in colorectal cancer (CRC).MethodsQuantitative real-time polymerase chain reaction (qPCR), western blotting analysis, the Cancer Genome Atlas (TCGA) data mining and immunohistochemistry were employed to examine IMPDH2 expression in CRC cell lines and tissues. A series of in-vivo and in-vitro assays were performed to demonstrate the function of IMPDH2 and its possible mechanisms in CRC.ResultsIMPDH2 was upregulated in CRC cells and tissues at both mRNA and protein level. High IMPDH2 expression was closely associated with T stage, lymph node state, distant metastasis, lymphovascular invasion and clinical stage, and significantly correlated with poor survival of CRC patients. Further study revealed that overexpression of IMPDH2 significantly promoted the proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) of CRC cells in vitro and accelerated xenograft tumour growth in nude mice. On the contrary, knockdown of IMPDH2 achieved the opposite effect. Gene set enrichment analysis (GSEA) showed that the gene set related to cell cycle was linked to upregulation of IMPDH2 expression. Our study verified that overexpressing IMPDH2 could promote G1/S phase cell cycle transition through activation of PI3K/AKT/mTOR and PI3K/AKT/FOXO1 pathways and facilitate cell invasion, migration and EMT by regulating PI3K/AKT/mTOR pathway.ConclusionsThese results suggest that IMPDH2 plays an important role in the development and progression of human CRC and may serve as a novel prognostic biomarker and therapeutic target for CRC.

Highlights

Inosine 5′-monophosphate dehydrogenase type II (IMPDH2) was originally identified as an oncogene in several human cancers
IMPDH2 is up-regulated in colorectal cancer (CRC) Real-time quantitative PCR and western blotting analysis showed that the levels of IMPDH2 expression were varied in FHC cells and seven CRC cell lines including HCT116, SW620, M5, SW480, HT29, DLD-1 and LoVo
IMPDH2 promoted the invasion and metastasis of CRC cells through EMT Based on the comparison between the IMPDH2-overexpressed cells (SW480/IMPDH2 and LoVo/IMPDH2) and their control groups, we found that IMPDH2 overexpression induced transdifferentiation of non-invasive epithelial cells to mesenchymal, spindle cells (Fig. 4a), demonstrating that IMPDH2 might be involved in epithelial-mesenchymal transition (EMT) of CRC cells, a crucial process characterized by tumor cell invasion and migration [19]

Summary

Introduction

Inosine 5′-monophosphate dehydrogenase type II (IMPDH2) was originally identified as an oncogene in several human cancers. The clinical significance and biological role of IMPDH2 remain poorly understood in colorectal cancer (CRC). Colorectal cancer (CRC) is one of the most common types of malignancies worldwide [1], and its incidence and mortality rates are continuously increasing. Inosine5′-monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme which catalyzes the nicotinamide adenine dinucleotide (NAD+)-dependent oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP), which is an essential step in de novo biosynthesis of guanine nucleotides [2]. Isoforms of IMPDH, IMPDH2, have been of particular interest to oncologists due to its roles in regulation of cell proliferation, cell differentiation, and chemoresistance [4, 8,9,10,11]

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Conclusion