Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0345904 (liver cancer)
 15,188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Excess lactate production due to enhanced aerobic glycolysis is characteristic of malignant cancers, which is also intimately associated with poor cancer prognoses. Although tumor-associated lactate contributes to all major steps in carcinogenesis, its action mechanism remains obscure. To understand the molecular mechanism of the lactate-induced tumor metastatic process, we identified an array of lactate-responsive genes via transcriptome analysis of a metformin-induced hyper-glycolytic liver cancer model. Gene set enrichment analysis suggested E2F-RB pathway as the dominant regulator of the lactate-induced gene expression. We experimentally verified that lactate indeed activates E2F-mediated transcription by promoting E2F1 protein accumulation through a posttranscriptional mechanism. Literature-based analysis of target pathways potentially modulated by 136 top-ranked genes indicated that genes functioning in cell-cell or cell-matrix communications dominate the lactate-induced gene expression. Especially, those regulating microtubule functions, including a group of kinesin family members, were significantly up-regulated in lactate- and E2F1-dependent manners. Depletion of E2F1 or kinesins (KIF2C, KIF18B, KIF20A) led to deformation of microtubule structures, impairing cell motility as much as the deficit in lactate production. These results indicate that E2F pathway activation by tumor-associated lactate and subsequent transcriptional activation of microtubule functions play crucial roles in tumor metastasis, providing mechanistic clues to cell motility-directed anti-cancer strategies.
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PMID:Lactate Activates the E2F Pathway to Promote Cell Motility by Up-Regulating Microtubule Modulating Genes. 3081 60

Kinesin superfamily proteins (KIFs) comprise a family of molecular motors that transport membranous organelles and protein complexes in a microtubule- and ATP-dependent manner, with multiple roles in cancers. Little is known about the function of KIFs in hepatocellular carcinoma (HCC). Here, we investigate the roles of KIFs in the prognosis and progression of HCC. Upregulation of eight KIFs (KIF2C, KIF4A, KIF10, KIF11, KIF14, KIF18B, KIF20A, and KIF23) was found to be significantly associated with the tumor stage and pathological tumor grade of HCC patients. Additionally, a high expression of these eight KIFs was significantly associated with shorter overall survival (OS) and disease-free survival (DFS) in patients with HCC. Cox regression analysis showed the mRNA expression levels of these eight KIF members to be independent prognostic factors for worse outcomes in HCC. Moreover, a risk score model based on the mRNA levels of the eight KIF members effectively predicted the OS rate of patients with HCC. Additional experiments revealed that downregulation of each of the eight KIFs effectively decreased the proliferation and increased the G1 arrest of liver cancer cells in vitro. Taken together, these results indicate that KIF2C/4A/10/11/14/18B/20A/23 may serve as prognostic biomarkers for survival and potential therapeutic targets in HCC patients.
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PMID:Kinesin family members KIF2C/4A/10/11/14/18B/20A/23 predict poor prognosis and promote cell proliferation in hepatocellular carcinoma. 3250 65