The Decrease of Mineralcorticoid Receptor Drives Angiogenic Pathways in Colorectal Cancer

Abstract

Angiogenesis plays a crucial role in tumor growth and progression. Low expression of mineralocorticoid receptor (MR) in several malignant tumors correlates with disease recurrence and overall survival. Previous studies have shown that MR expression is decreased in colorectal cancer (CRC). Here we hypothesize that decreased MR expression can contribute to angiogenesis and poor patient survival in colorectal malignancies. In a cohort of CRC patients, we analyzed tumor MR expression, its correlation with tumor microvascular density and its impact on survival. Subsequently, we interrogated the role of MR in angiogenesis in an in vitro model, based on the colon cancer cell line HCT116, ingenierized to re-express a physiologically controlled MR. In CRC, decreased MR expression was associated with increased microvascular density and poor patient survival. In pchMR transfected HCT116, aldosterone or natural serum steroids largely inhibited mRNA expression levels of both VEGFA and its receptor 2/KDR. In CRC, MR activation may significantly decrease angiogenesis by directly inhibiting dysregulated VEGFA and hypoxia-induced VEGFA mRNA expression. In addition, MR activation attenuates the expression of the VEGF receptor 2/KDR, possibly dampening the activation of a VEGFA/KDR dependent signaling pathway important for the survival of tumor cells under hypoxic conditions.

A Novel MIF Signaling Pathway Drives the Malignant Character of Pancreatic Cancer by Targeting NR3C2

“…The functional role of NR3C2 in tumorigenesis is not clear. An association between lower NR3C2 expression and increased angiogenesis has been described in colon cancer (19). EMT is a critical event in the progression of pancreatic cancer.…”

“…Interestingly, a decrease in NR3C2 expression is associated with poor prognosis in lung and colorectal cancer (18, 19). However, the role of NR3C2 has not been described in pancreatic cancer.…”

“…NR3C2 is a mineralocorticoid receptor gene encoding mineralocorticoid receptor (MR), which functions as a transcription factor and plays a crucial role in regulating electrolyte balance (29). Interestingly, a lower expression of MR predicted poor prognosis in lung and colon cancer patients (18,19). To our knowledge the role of NR3C2 has not been described in pancreatic cancer.…”

Low NR3C2 levels correlate with aggressive features and poor prognosis in non‐distant metastatic clear‐cell renal cell carcinoma

“…Nie et al () found that activation of NR3C2 could inhibit the Warburg effect in hepatocellular carcinoma by modulating miR‐338‐3p/pyruvate kinase. In colorectal cancer, some studies have demonstrated that decreased MR expression is associated with increased microvascular density and poor patient survival through the direct inhibition of dysregulated VEGFA expression (Di Fabio et al, ; Tiberio et al, ). Similar results have also been demonstrated in early stage cervical carcinoma (Huang et al, ), pancreatic cancer (Yang et al, ), breast cancer (Nan, Dorgan, & Rebbeck, ), and lung cancer (Jeong et al, ).…”

Investigating the Role of Mineralocorticoid Receptor Signaling in Cancer Biology in the Genomic Era

“…In colon cancer, an observed decrease in the expression of MR in cancerous tissue in comparison to the adjacent normal mucosa has attributed MR a tumor suppressive role [6]. Tiberio et al [7] further investigated how MR expression correlated with patient survival in colorectal carcinomas. In this study, the expressions of MR and tumor microvessel density marker protein CD34 were evaluated in tumor and normal colorectal mucosa by IHC, and an inverse correlation of expression was detected between them in colorectal cancers.…”