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

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.

<p>FNDC3B, Targeted by miR-125a-5p and miR-217, Promotes the Proliferation and Invasion of Colorectal Cancer Cells via PI3K/mTOR Signaling</p>

“…accelerated the migration and invasion of tumor cells. 31 Our present study also addressed the evidence that FNDC3B exerted positive effects on the activation of PI3K/mTOR signaling during promoting CRC cell processes. Contrarily, there was evidence suggested that mTOR inactivation could enhance cellular autophagy, which may be a protective measure for the survival of tumor cells.…”

Expression of miR‐486‐5p and its significance in lung squamous cell carcinoma

“…In the current study, we not only focused on the function of predicted target genes, but also combined the all genes of LUSC according to their correlation with miR‐486‐5p expression to understand the molecular functions. Among these function, the PI3K‐AKT signaling pathways, over activating in multiple cancers, was a central regulatory point in the process of cell proliferation, growth and differentiation, which was both predicted in GSEA and KEGG analysis . Moreover, we identified three important transcription factors (RUNX2, HOXD8, and HNF1A) that may influence significantly LUSC.…”

Metabolic Compartmentalization at the Leading Edge of Metastatic Cancer Cells

“…In human fibroblasts, inhibiting IMPDH via MPA treatment was shown to lead to decreased adhesion and migration along with dysregulated cytoskeletal proteins (65). Similarly, MPA treatment led to a decrease in the migration and invasion of gastric cancer cells in vitro (66) and to a decrease in the EMT, in vitro migration, and metastatic seeding of prostate cancer cells (67). IMPDH inhibition was reported to decrease the fraction of GTP-bound RAC1, RHOA, and RHOC, the molecular switch proteins responsible for polarizing cells during migration (68), in melanoma cells (69).…”