RASSF10 is frequently epigenetically inactivated in kidney cancer and its knockout promotes neoplasia in cancer prone mice

Abstract

Kidney cancer incidences are rising globally, thereby fueling the demand for targeted therapies and precision medicine. In our previous work, we have identified and characterized the Ras-Association Domain Family encoding ten members that are often aberrantly expressed in human cancers. In this study, we created and analyzed the Rassf10 knockout mice. Here we show that Rassf10 haploinsufficiency promotes neoplasia formation in two established mouse cancer models (Rassf1A −/− and p53 −/−). Haploinsufficient Rassf10 knockout mice were significantly prone to various diseases including lymphoma (Rassf1A −/− background) and thymoma (p53 −/− background). Especially Rassf10 −/− and p53-deficient mice exhibited threefold increased rates of kidney cysts compared with p53 −/− controls. Moreover, we observed that in human kidney cancer, RASSF10 is frequently epigenetically inactivated by its CpG island promoter hypermethylation. Primary tumors of renal clear cell and papillary cell carcinoma confirmed that RASSF10 methylation is associated with decreased expression in comparison to normal kidney tissue. In independent data sets, we could validate that RASSF10 inactivation clinically correlated with decreased survival and with progressed disease state of kidney cancer patients and polycystic kidney size. Functionally, we revealed that the loss of Rassf10 was significantly associated with upregulation of KRAS signaling and MYC expression. In summary, we could show that Rassf10 functions as a haploinsufficient tumor suppressor. In combination with other markers, RASSF10 silencing can serve as diagnostic and prognostic cancer biomarker in kidney diseases.

RETRACTED: Oncogenic miR-27a delivered by exosomes binds to SFRP1 and promotes angiogenesis in renal clear cell carcinoma

“… 25 , 26 Cancers of the kidney are accompanied by a high and rising morbidity across the globe, and there is an urgent sense that improvements must now come from fresh approaches. 27 The current study has provided evidence reporting that miR-27a accelerated angiogenesis of HUVECs by downregulating SFRP1 expression. The high expression of miR-27a has been found to augment sprout formation in endothelial cells and then angiogenesis through stimulating the repulsion of neighboring endothelial cells.…”

Immune profile of the tumor microenvironment and the identification of a four-gene signature for lung adenocarcinoma

“…To a certain extent, this result also indicated that the immune microenvironment of LUAD is an important factor affecting tumor immunotherapy. Although there are many research reports on screening tumor prognostic markers [ 40 – 42 ], research on the correlation between these markers and TIICs in the TME of LUAD is scarce. To elucidate the mechanism underlying the functions of CCR2, CCR4, P2RY12, and P2RY13 in immune microenvironment of LUAD, we performed GSEA and correlation analysis.…”

Epigenetic regulation in human cancer: the potential role of epi-drug in cancer therapy

“…Hypermethylation of promoters in CGIs is the most recognised mechanism of epigenetic alterations in cancer cells and has been well implicated in various cancer types. Abundant TSGs are under hypermethylation, such as RASSF10 in kidney cancer [42], SIX3 in glioblastoma [43], CDKN2A and PTEN in melanoma [44,45], etc. Besides, not only TSGs hypermethylation is commonly seen in many cancers, but additional genes involved in multiple pivotal cellular functions also present hypermethylation.…”