miR‐144‐3p/miR‐451a promotes lymphovascular invasion through repression of PTEN/p19 in rectal neuroendocrine tumors

Abstract

Background and Aim: Although rectal neuroendocrine tumor (NET-G1) have potential metastatic capability, even among small tumors, no predictive biomarker for invasion and metastasis has been reported. We analyzed microRNA (miRNA) expression profiles in rectal NET-G1 tissues with and without lymphovascular invasion (LVI). Moreover, we then investigated their target genes to clarify the mechanism of invasion/metastasis in NET-G1. Methods: miRNA array analysis was performed using seven rectal NET-G1 tissues with LVI and seven without LVI. miRNA expression was confirmed by quantitative real-time PCR. A NET cell line H727 was transfected with miRNA mimic or target gene small interfering RNA, and migration and invasion assays were performed. Results:The expression levels of miR-144-3p and miR-451a were significantly higher in NET-G1 with LVI versus without LVI, as determined by miRNA array analysis and RT-qPCR. A significant correlation was observed between miR-144-3p and miR-451a expression levels, strongly suggesting miR144/451 cluster overexpression in NET-G1 with LVI. Bioinformatic analysis of target genes revealed that miR-144-3p and miR-451a directly interact with PTEN and p19 mRNA, respectively. Immunohistochemistry revealed significantly lower expression of PTEN and p19 in NET-G1 tissues with LVI than in those without LVI. The miR-144-3p and miR-451a mimic significantly increased cell migration/invasion capability, respectively. Knockdown of PTEN and p19 induced significant augmentation of cell invasion and migration capability, respectively. Conclusions: Our data suggest that overexpression of miR-144/miR-451 cluster promotes LVI via repression of PTEN and p19 in rectal NET-G1 cells. miR-144/451 cluster may be a novel biomarker for predicting invasion/metastasis in rectal NET-G1.

Preoperative red cell distribution width is associated with postoperative lymphovascular invasion in prostate cancer patients treated with radical prostatectomy: A retrospective study

“…Furthermore, several studies have observed that LVI could mirror lymph node invasion status ( 13 ), and was associated with unfavorable biochemical recurrence (BCR) rates and overall survival after RP ( 11 , 12 , 14 , 15 ). The underlying mechanism of LVI remains unclear although some recent studies tried to reveal it from genetic level ( 16 – 18 ). It involves not only the acquisition of more invasive and migration abilities of the malignant epithelial cells but also the interaction with the surrounding tumor microenvironment (TME) along with endothelial cells lining the lymphovascular spaces ( 19 ).…”

Identification of the targeted mRNA associated with the miRNA microarray of chemo-sensitive choriocarcinoma using bioinformatics analysis

“…Among the 18 hub genes, PTEN was simultaneously found to have the highest interaction degree with the top 3 most overexpressed and underexpressed miRNAs, suggesting that PTEN may participate in transcription from the RNA polymerase II promoter and negative regulation of apoptotic processes to lead to cell proliferation and apoptosis. Moreover, a previous study stated that miR-144-3p can target PTEN to promote lymphovascular invasion, proliferation, and cardiac brosis in rectal neuroendocrine tumours, thyroid tumours, and myocardial infarction (44)(45)(46). As a cancer suppressor, PTEN, which is a dual protein/lipid phosphatase that can inhibit the PIP3/PI3K/AKT signalling pathway, plays important roles in carcinogenesis (47), and mutations in this gene may be utilized as targets of treatment of chemosensitive CC.…”

Exosomal microRNA signature from plasma-derived extracellular vesicles in gastric cancer

“…In EVs, hsa-miR-451a was described by Yoshida et al in bile-derived exosomes from patients with biliary tract cancers (BTCs) and functioning as a potential biomarker of these diseases [31]. Like miRNA-92a-3p, hsa-miR-451a also targets and suppresses the expression of the PTEN tumor suppressor in neuroendocrine tumors of the rectum, generating invasion and metastasis [32].…”