Functional characterization of Trip10 in cancer cell growth and survival

Abstract

BackgroundThe Cdc42-interacting protein-4, Trip10 (also known as CIP4), is a multi-domain adaptor protein involved in diverse cellular processes, which functions in a tissue-specific and cell lineage-specific manner. We previously found that Trip10 is highly expressed in estrogen receptor-expressing (ER+) breast cancer cells. Estrogen receptor depletion reduced Trip10 expression by progressively increasing DNA methylation. We hypothesized that Trip10 functions as a tumor suppressor and may be involved in the malignancy of ER-negative (ER-) breast cancer. To test this hypothesis and evaluate whether Trip10 is epigenetically regulated by DNA methylation in other cancers, we evaluated DNA methylation of Trip10 in liver cancer, brain tumor, ovarian cancer, and breast cancer.MethodsWe applied methylation-specific polymerase chain reaction and bisulfite sequencing to determine the DNA methylation of Trip10 in various cancer cell lines and tumor specimens. We also overexpressed Trip10 to observe its effect on colony formation and in vivo tumorigenesis.ResultsWe found that Trip10 is hypermethylated in brain tumor and breast cancer, but hypomethylated in liver cancer. Overexpressed Trip10 was associated with endogenous Cdc42 and huntingtin in IMR-32 brain tumor cells and CP70 ovarian cancer cells. However, overexpression of Trip10 promoted colony formation in IMR-32 cells and tumorigenesis in mice inoculated with IMR-32 cells, whereas overexpressed Trip10 substantially suppressed colony formation in CP70 cells and tumorigenesis in mice inoculated with CP70 cells.ConclusionsTrip10 regulates cancer cell growth and death in a cancer type-specific manner. Differential DNA methylation of Trip10 can either promote cell survival or cell death in a cell type-dependent manner.

Defining functional interactions during biogenesis of epithelial junctions

“…VAV2 is an activator (exchange factor) of Rho GTPases42 and the latter have important roles in different steps of junction assembly, maturation and disruption. The partnership of VAV2 and TRIP10 identified here is functionally and clinically relevant, as both have important functions in epithelial differentiation and morphogenesis43444546, and participate in oncogenic pathways leading to cell invasion3247484950.…”

Alternative polyadenylation drives oncogenic gene expression in pancreatic ductal adenocarcinoma

“…Amongst the genes found to have significantly shortened 3’-UTR lengths were many known PDA growth-promoting genes, including PAF1 (Polymerase Associated Factor 1), FLNA (Filamin-A), ENO1 (α Enolase), RALGDS (Ral guanine nucleotide dissociation stimulator), TRIP10 (Thyroid Hormone Receptor Interactor 10) and ALDOA (Aldolase A). ALDOA and PAF1 have recently been described as oncogenes in PDA 50–53 , while ENO1, RALGDS, TRIP10 and FLNA are known to mediate pancreatic cancer cell proliferation, survival and migration 54–59 . We did not detect 3’-UTR alterations in recurrently mutated PDA genes, reflecting the predominant role of APA in regulating gene expression rather than gene function.…”

Expression of Migration-Related Genes in Human Colorectal Cancer and Activity of a Disintegrin and Metalloproteinase 17

“…Existing data on the prognostic role of metalloproteinases and their inhibitors as markers of progression of colorectal cancer are ambiguous. Increased activity of MMP2 and MMP9 seems to play a key role in the growth and invasion of tumor and its metastasis [ 17 ]. MMP9 is particularly interesting, since a basic level of expression in most cells is generally low, whereas it is highly expressed in most human cancers and responds to growth factors and cytokines [ 18 ].…”