PTEN/MMAC1 was also identified as the gene predisposing to Cowden disease, an autosomal dominant cancer predisposition syndrome associated with an increased risk of breast, skin and thyroid tumors and occasional cases of other cancers including bladder and renal cell carcinoma.
Because loss of PTEN can activate mTOR and mTOR inhibitors are Food and Drug Administration approved to treat renal cell carcinoma, these agents have clinical potential in renal cell carcinoma associated with Cowden syndrome.
Depletion of the triggering receptor expressed on myeloid cells 2 inhibits progression of renal cell carcinoma via regulating related protein expression and PTEN-PI3K/Akt pathway.
Expression levels of PTEN-Long in serum of patients with nephritis, renal cell carcinoma (RCC) as well as normal controls, and in serum and renal tissues of mice were measured by western blotting.
Further studies verified that PTEN deficiency effectively attenuated the ability of AFAP1-AS1 in promoting ccRCC cell proliferation, invasion, migration, and EMT.
Furthermore, 19 of 20 advanced RCC showed somatic hypermethylation upstream of KILLIN, with the majority hypermethylated at more than one CpG island (13/19 vs. 3/23 with germline methylation, P < 0.0001). qRT-PCR revealed that methylation significantly downregulates KILLIN expression (P = 0.05), and demethylation treatment by 5-aza-2'deoxycytidine significantly increased KILLIN expression in all RCC cell lines while only increasing PTEN expression in one line.
Gain of function experiments showed overexpression of PTEN-Long in the ccRCC cell line 786-0 suppressed PI3K-Akt signaling, inhibited cell proliferation, migration and invasion, and eventually induced cell death.
In ccRCC tissues, expression levels of SMAD4 and PTEN were negatively correlated with expression level of miR-19a, revealing that miR-19a suppressed the expression of SMAD4 and PTEN in ccRCC patients. miR-19a overexpression significantly suppressed the expression of SMAD4 and PTEN in vitro, further verifying that SMAD4 and PTEN were the target genes of miR-19a in ccRCC cells.
Other genes involved in regulating hypoxia-inducible factor [e.g. genes encoding carbonic anhydrase-IX and PTEN (phosphatase and tensin homolog)] were reported to be prognostically important in renal cell carcinoma.
Our findings have indicated that multiple genes and pathways may play a crucial role in PTEN mutation ccRCC, offering candidate targets and strategies for PTEN mutation ccRCC individualized treatment.
PTENP1 and PTEN are direct targets of miRNA miR21 and their expression is suppressed by miR21 in ccRCC cell lines. miR21 expression promotes ccRCC cell proliferation, migration, invasion in vitro, and tumor growth and metastasis in vivo.
Taken together, the findings indicated for the first time that miR-193a-3p functions as a tumor-promoting microRNA by directly targeting PTEN in renal cell carcinoma.