Impaired AGO2/miR-185-3p/NRP1 axis promotes colorectal cancer metastasis

Abstract

Increasing evidence suggests that global downregulation of miRNA expression is a hallmark of human cancer, potentially due to defects in the miRNA processing machinery. In this study, we found that the protein expression of Argonaute 2 (AGO2), a key regulator of miRNA processing, was downregulated in colorectal cancer (CRC) tissues, which was also consistent with the findings of the Clinical Proteomic Tumor Analysis Consortium (CPTAC). Furthermore, the correlation between the levels of AGO2 and epithelial-mesenchymal transition (EMT) markers (E-cadherin and vimentin) indicated that reduced levels of AGO2 promoted EMT in CRC. Low expression of AGO2 was an indicator of a poor prognosis among CRC patients. Knockdown of AGO2 in CRC cells promoted migration, invasion and metastasis formation in vitro and in vivo but had no influence on proliferation. To provide detailed insight into the regulatory roles of AGO2, we performed integrated transcriptomic, quantitative proteomic and microRNA sequencing (miRNA-seq) analyses of AGO2 knockdown cells and the corresponding wild-type cells and identified neuropilin 1 (NRP1) as a new substrate of AGO2 via miR-185-3p. Our data provided evidence that knockdown of AGO2 resulted in a reduction of miR-185-3p expression, leading to the upregulation of the expression of NRP1, which is a direct target of miR-185-3p, and elevated CRC cell metastatic capacity. Inhibition of NRP1 or treatment with a miR-185-3p mimic successfully rescued the phenotypes of impaired AGO2, which suggested that therapeutically targeting the AGO2/miR-185-3p/NRP1 axis may be a potential treatment approach for CRC.

Neuropilin-1 as a Potential Biomarker of Prognosis and Invasive-Related Parameters in Liver and Colorectal Cancer: A Systematic Review and Meta-Analysis of Human Studies

“…As in meta-regression results, sample size seemed to be a useful moderator for removing heterogeneity. Moreover, the removal of two out of the seven CRC studies [ 22 , 33 ] also resolved heterogeneity (I 2 = 36.07%, Q-test p = 0.18), not showing a significant correlation (HR 1.01, 95% CI 1.00–1.02, p = 0.10) again ( Table 3 B). Notwithstanding, when OS and NRP1 association was analyzed within liver cancer studies, different results were obtained after subgroup analysis ( Table 3 C).…”

“…An electronic search was performed in five major databases, identifying a total of 728 articles. After duplicate removal ( n = 371), screening by title and abstract ( n = 174) and full-text screening ( n = 168), 15 eligible articles were finally included for data extraction and quantitative analysis [ 14 , 16 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. Out of the 15 studies, six were conducted in CRC patients, eight in liver cancer patients (specifically six in HCC patients and two in CCA patients), and one was a pan-cancer study that included all the tumor types ( Figure 1 ).…”

“…In this meta-analysis, patients subjected to surgery as well as patients in which no intervention was done were included. Even though subgroups based on this parameter could provide a useful analysis for assessing the heterogeneity source, thus separating patients with and without (R0 resected) cancer for OS, this subgroup analysis could not be performed due to missing data about the intervention made to patients in some of the included studies [ 29 , 33 ].…”

“… Forest plots showing HR for the association between NRP1 overexpression and OS among ( a ) all included studies, [ 21 , 22 , 23 , 24 , 25 , 28 , 29 , 30 , 31 , 32 , 33 ] ( b ) separately CRC and liver cancer studies, and ( c ) separately for CCA, CRC and HCC studies. CCA, cholangiocarcinoma; CI, confidence interval; CRC, colorectal cancer; HCC, hepatocellular carcinoma; HR, hazard ratio; LC, liver cancer; OS, overall survival; REML, Restricted Maximum Likelihood.…”

The novel circSLC6A6/miR-1265/C2CD4A axis promotes colorectal cancer growth by suppressing p53 signaling pathway

“…Numerous studies confirmed that aberrantly expressed miRNAs had regulated CRC development and progression [ 41 , 42 ]. The biological function of miR-1265 widely considered as a tumor-suppressive role in several cancers and its molecular targets in the process of tumorigenesis had been illustrated in several studies [ 27 , 28 , 33 ].…”