RUNX2 overexpression and PTEN haploinsufficiency cooperate to promote CXCR7 expression and cellular trafficking, AKT hyperactivation and prostate tumorigenesis

Abstract

Rationale: The overall success rate of prostate cancer (PCa) diagnosis and therapy has been improved over the years. However, genomic and phenotypic heterogeneity remains a major challenge for effective detection and treatment of PCa. Efforts to better classify PCa into functional subtypes and elucidate the molecular mechanisms underlying prostate tumorigenesis and therapy resistance are warranted for further improvement of PCa outcomes. Methods: We generated Cre + ; Runx2- cTg; Pten p/+ ( Runx2-Pten double mutant) mice by crossbreeding Cre + ; Runx2- cTg males with Pten conditional ( Pten p/p ) females. By using Hematoxylin and Eosin (H&E) staining, SMA and Masson's Trichrome staining, we investigated the effect of PTEN haploinsufficiency in combination with Runx2 overexpression on prostate tumorigenesis. Moreover, we employed immunohistochemistry (IHC) to stain Ki67 for cell proliferation, cleaved caspase 3 for apoptosis and AKT phosphorylation for signaling pathway in prostate tissues. Chromatin immunoprecipitation coupled quantitative PCR (ChIP-qPCR), reverse transcription coupled quantitative PCR (RT-qPCR), western blot (WB) analyses and immunofluorescence (IF) were conducted to determine the underlying mechanism by which RUNX2 regulates CXCR7 and AKT phosphorylation in PCa cells. Results: We demonstrated that mice with prostate-specific Pten heterozygous deletion and Runx2 overexpression developed high-grade prostatic intraepithelial neoplasia (HGPIN) and cancerous lesions at age younger than one year, with concomitant high level expression of Akt phosphorylation and the chemokine receptor Cxcr7 in malignant glands. RUNX2 overexpression induced CXCR7 transcription and membrane location and AKT phosphorylation in PTEN-deficient human PCa cell lines. Increased expression of RUNX2 also promoted growth of PCa cells and this effect was largely mediated by CXCR7. CXCR7 expression also positively correlated with AKT phosphorylation in PCa patient specimens. Conclusions: Our results reveal a previously unidentified cooperative role of RUNX2 overexpression and PTEN haploinsufficiency in prostate tumorigenesis, suggesting that the defined RUNX2-CXCR7-AKT axis can be a viable target for effective treatment of PCa.

TRIM37 Mediates Chemoresistance and Maintenance of Stemness in Pancreatic Cancer Cells via Ubiquitination of PTEN and Activation of the AKT–GSK-3β–β-Catenin Signaling Pathway

“…PTEN is mutated in numerous cancers and has been extensively investigated for its role as a tumor suppressor by negative regulation of AKT signaling in multiple cancers (35)(36)(37)(38). Here, we identified an inverse relationship between the expression of TRIM37 and PTEN in clinical PC specimens, which is consistent with TRIM37-mediated regulation of PTEN degradation.…”

Ovarian cancer cell-secreted exosomal miR-205 promotes metastasis by inducing angiogenesis

“…PTEN is a key mediator of the PI3K/AKT pathway, which plays an essential role in the formation of normal blood vessels during development 35. Frequent activation of AKT signalling can result in uncontrolled proliferation and neoplastic angiogenesis, and PTEN is a phosphatase necessary for the specific and effective termination of oncogenic AKT signalling induced by oncogenes 36, 37. According to our results, ectopic expression of miR-205 dramatically decreased PTEN both at the mRNA and protein levels and increased that of p-AKT in HUVECs.…”

The Role of the CXCL12/CXCR4/CXCR7 Chemokine Axis in Cancer

“…Furthermore, other transcription factors have also been suggested to increase mRNA and protein of CXCR4 in cancer development, including Runt-related transcription factor 2 (RUNX2) ( Guo et al, 2016 ) and POU1F1transcription factor (Pit-1) ( Martinez-Ordoñez et al, 2018 ). Similarly, overexpression of RUNX2 can induce CXCR7 transcription in prostate cancer ( Bai et al, 2019 ). Another study demonstrated that CXCR7 expression had been upregulated by interleukin 6 (IL6) that is mainly derived from cancer-associated fibroblasts, contributing to chemoresistance in esophageal squamous cell carcinoma ( Qiao et al, 2018 ).…”