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


METHODS
Quantitative 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.


RESULTS
IMPDH2 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.


CONCLUSIONS
These 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.
['Duan|Shiyu|S|', 'Huang|Wenqing|W|', 'Liu|Xiaoting|X|', 'Liu|Xuming|X|', 'Chen|Nana|N|', 'Xu|Qiong|Q|', 'Hu|Yukun|Y|', 'Song|Wen|W|', 'Zhou|Jun|J|']
D000818:Animals D049109:Cell Proliferation D015179:Colorectal Neoplasms D018450:Disease Progression D005260:Female D000071161:Forkhead Box Protein O1 D045325:HCT116 Cells D057809:HEK293 Cells D064593:Heterografts D006801:Humans D007168:IMP Dehydrogenase D008297:Male D051379:Mice D008819:Mice, Nude D019869:Phosphatidylinositol 3-Kinases D051057:Proto-Oncogene Proteins c-akt D015398:Signal Transduction D058570:TOR Serine-Threonine Kinases D014162:Transfection
IMPDH2 Colorectal cancer Proliferation EMT Cell cycle