Dysregulation of the miR-25-IMPA2 axis promotes metastatic progression in clear cell renal cell carcinoma

Abstract

Background The molecular mechanism underlying clear cell renal cell carcinoma (ccRCC) metastasis remains unclear. We therefore aimed to elucidate the role of IMPA2 in ccRCC metastatic progression. Methods Using the Cancer Genome Atlas (TCGA) database and immunohistochemistry (IHC) staining, we investigated differences in IMPA2 mRNA and protein expression, as well as their clinical relevance, in ccRCC. To investigate the function of IMPA2 in ccRCC metastasis, we performed in vitro migration and in vivo lung colony-forming assays. We further explored the effect of microRNA (miR)-25 on IMPA2 expression by performing a luciferase reporter assay. Findings We show that ccRCC expresses relatively lower transcript levels of IMPA2 than normal kidney tissue. IMPA2 downregulation was greater in high-grade ccRCC than in low-grade ccRCC and was correlated with a poor prognosis in ccRCC patients. Importantly, we demonstrate that IMPA2 expression is inversely associated with the metastatic potential of ccRCC cells. We found that IMPA2 knockdown promotes, but overexpression suppresses, the cellular migration and lung colony-forming abilities of ccRCC cells. By using in silico and luciferase reporter assays, we found that IMPA2 expression is primarily influenced by miR-25 in ccRCC cells. Significantly, the inhibition of miR-25 function restored IMPA2 expression, thereby diminishing the metastatic potential of ccRCC cells. Interpretation We conclude that miR-25-mediated IMPA2 downregulation constitutes a novel signature for cancer metastasis and poor outcomes in ccRCC. We further postulate that the therapeutic targeting of miR-25 can be useful for preventing the metastatic progression of ccRCC associated with IMPA2 downregulation. Fund This study was supported by the Ministry of Science and Technology, Taiwan (MOST 107-2314-B-038-094, MOST 106-2314-B-038-069-MY3, MOST 105-2320-B-038-021-MY3 and MOST 107-2320-B-038-056).

A novel function of IMPA2, plays a tumor-promoting role in cervical cancer

“…However, there is only one published article clearly demonstrated the relationship between IMPA2 expression and cancer progression. Lin et al recently showed that IMPA2 downregulation constitutes a novel signature for cancer metastasis and poor outcomes in ccRCC 15 . On the contrary, our data of RNA sequencing (RNA-seq) showed an obvious upregulation of IMPA2 in cervical cancer.…”

“…Recently, French et al 14 found that IMPA2 expression might affect accumulation of methotrexate polyglutamates (MTXPGs) in leukemia. In addition, Lin et al 15 indicated that IMPA2 downregulation leads to poor outcomes in clear cell renal cell carcinoma (ccRCC). This is contrary to our speculation on the role of IMPA2 in cervical cancers.…”

Ubiquitin specific peptidase 19 is a prognostic biomarker and affect the proliferation and migration of clear cell renal cell carcinoma

“…The remaining 30% of RCC subtypes, such as chromophobe and papillary RCC, are generally indolent (3). Surgery is the most effective treatment for ccRCC, as chemotherapy and radiotherapy are not as successful in controlling its progression; however, ~25% of clinical patients with ccRCC will develop metastatic disease despite curative surgical removal of the primary tumor (4). The overall 5-year survival rate of RCC patient is 5-10%, with a median survival of only ~13 months (5).…”

A Review of Recent Research on the Role of MicroRNAs in Renal Cancer

“…Recent research suggests that IMPA2 (inositol monophosphotase 2) leads to decreasing p-mTORC1 levels in ccRCC cells, and thus could be a biomarker for guiding the use of mTOR inhibitors to combat metastatic ccRCC in clinical practice [ 67 ]. Indeed, IMPA2 underexpression in ccRCC diminishes the expression of N-cadherin and Slug, and sabotages tumor metastasis by downregulating miR-25-3p [ 68 ]. Dysregulated cellular energetics is one of the hallmarks of RCC and of multiple cancers [ 47 ].…”