Quaking orchestrates a post-transcriptional regulatory network of endothelial cell cycle progression critical to angiogenesis and metastasis

Abstract

Angiogenesis is critical to cancer development and metastasis. However, anti-angiogenic agents have only had modest therapeutic success, partly due to an incomplete understanding of tumor endothelial cell (EC) biology. We previously reported that the microRNA (miR)-200 family inhibits metastasis through regulation of tumor angiogenesis, but the underlying molecular mechanisms are poorly characterized. Here, using integrated bioinformatics approaches, we identified the RNA-binding protein (RBP) quaking (QKI) as a leading miR-200b endothelial target with previously unappreciated roles in the tumor microenvironment in lung cancer. In lung cancer samples, both miR-200b suppression and QKI overexpression corresponded with tumor ECs relative to normal ECs, and QKI silencing phenocopied miR-200b-mediated inhibition of sprouting. Additionally, both cancer cell and endothelial QKI expression in patient samples significantly corresponded with poor survival and correlated with angiogenic indices. QKI supported EC function by stabilizing cyclin D1 (CCND1) mRNA to promote EC G1/S cell cycle transition and proliferation. Both nanoparticle-mediated RNA interference of endothelial QKI expression and palbociclib blockade of CCND1 function potently inhibited metastasis in concert with significant effects on tumor vasculature. Altogether, this work demonstrates the clinical relevance and therapeutic potential of a novel, actionable miR/RBP axis in tumor angiogenesis and metastasis.

MicroRNAs as Potential Predictors of Response to CDK4/6 Inhibitor Treatment

“…Overall, 16 articles were identified and screened. After removal of 2 irrelevant studies [38,39] and 1 non-eligible article [37], 13 articles were considered eligible for our study [40][41][42][43][44][45][46][47][48][49][50][51][52]. A thorough search in ClinicalTrials.gov (access date on 1 January 2021) for additional studies retrieved no eligible studies.…”

“…miR-200b was shown to negatively regulate the expression of quaking (QKI), an RNA-binding protein that implicates in endothelial maturation and proliferation. Overexpression of miR-200b inhibited tumor angiogenesis through downregulation of QKI in tumor endothelium [50]. Subsequently, QKI was shown to directly bind to and stabilize cyclin D1 (CCND1) mRNA.…”

“…This novel miR200b/QKI/CCND1 axis played a role in tumor angiogenesis via the CCND1-mediated endothelial cell cycle progression. Palbociclib inhibited endothelial cell proliferation and tumor angiogenesis by disrupting the CDK4/6-cyclin D complex, thus the miR200b/QKI/CCND1 axis [50]. Palbociclib treatment resulted in a decreased metastatic ability in vivo in tumor-bearing mouse models [50].…”

RBM45 Promoted HCC Growth and Metastasis by Stabilizing BCL2 and Twist1 mRNA

“…RNA binding proteins (RBPs), the main undertaker of post-transcriptional regulatory process, are critical in RNA fate determination via regulating RNA splicing, nuclear export, degradation, stabilization and translation [3] . Recently, RBPs has been implicated as a critical regulator of an important series of cancer-related genes [4][5][6] . The dysregulation of RBPs has been shown to impact HCC carcinogenesis and progression [7][8][9] .…”

LncRNA HCG11/miR‐26b‐5p/QKI5 feedback loop reversed high glucose‐induced proliferation and angiogenesis inhibition of HUVECs

“…It plays an important regulatory role in accumulating ECs and to induce angiogenesis. Azam SH et al found that endothelial QKI‐5 expression remarkably correlated with angiogenic indices 21 . Cochrane A et al found that the mouse ECs overexpressing QKI‐5 significantly improved angiogenesis and neovascularization and blood flow recovery in experimental hind limb ischaemia.…”