miR-181a-2* expression is different amongst carcinomas from the colorectal serrated route

Abstract

<jats:title>Abstract</jats:title> <jats:p>Serrated adenocarcinoma (SAC) and colorectal carcinomas showing histological and molecular features of high-level of microsatellite instability (hmMSI-H) are both end points of the serrated pathway of colorectal carcinogenesis. Despite common features (right-sided location, CpG island methylation phenotype and BRAF mutation) there are no studies comparing the microRNA (miRNA) expression profiles in SACs and hmMSI-H. The microtranscriptome from 12 SACs and 8 hmMSI-H were analysed using Affymetrix GeneChip miRNA 3.0 arrays and differentially enriched functions involving immune response were observed from this comparison. miR-181a-2* was found significantly more expressed in hmMSI-H than in SAC and higher expression of this miRNA in microsatellite unstable colorectal cancer were corroborated by Real-Time PCR in an extended series (61 SAC, 21 hmMSI-H). An analysis of genes possibly regulated by miR-181a-2* was carried out and, amongst these, an inverse correlation of NAMPT with miR-181a-2* expression was observed, whereas, for TRAF1 and SALL1, additional regulation mechanisms involving CpG island methylation were observed. miR-181a-2* is associated with particular histological and molecular features of colorectal carcinomas within the serrated pathological pathway and might play a role in the immune responses of microsatellite instability carcinomas.</jats:p>

Biology and Therapeutic Targets of Colorectal Serrated Adenocarcinoma; Clues for a Histologically Based Treatment against an Aggressive Tumor

“…The study of the microtranscriptome has shown a difference in the expression of miR-181-a2, which is lower in SAC than in hmMSI-H. The lower levels of this mircroRNA regulate the immune response by enhancing the expression of IL-2, IL-22 and IL-17a in the serrated lesions, which then might favor an immunosuppressive phenotype [28,97]. These differences confirm the importance of understanding the immune environment in SAC.…”

“…is a significantly lower presence of peritumoral and intratumoral lymphocytic infiltrates [18]. This poorer immune response of SAC is even more dramatic when compared to hmMSI-H, and therefore, transcriptome, micro-transcriptome and methylome studies have supported this histological observation [6,27,28]. These facts, added to the fact that most SACs are microsatellite-stable [2,3], do not make SAC a good candidate for biological therapy targeting the immune-checkpoint.…”

Transcription Factors: The Fulcrum Between Cell Development and Carcinogenesis

“…For instance, Sall1 was found to be a potential target of the oncogenic miR-4286 in prostate cancer whereby miR-4286 knockdown abrogated Sall1’s ability to induce apoptosis and inhibit proliferation. Another study reported an inverse correlation, although not significant, between Sall1 and the oncogenic miR-181a-2 that is involved in microsatellite instability ( 146 ). Table 2 highlights SAL1 expression in cancer modulation.…”

Global Methylome Scores Correlate with Histological Subtypes of Colorectal Carcinoma and Show Different Associations with Common Clinical and Molecular Features

“…The clinical and pathological characteristics of the study patients were reported previously [13][14][15][16][17]. This study was approved by the Local Ethical Boards from participating hospitals (Ref: PI12-01232), in agreement with the ethical principles laid down in the 1964 Declaration of Helsinki.…”