Overexpression of miR‑221 and miR‑222 in the cancer stroma is associated with malignant potential in colorectal cancer

Abstract

The cancer stroma is important in cancer development, however, whether the aberrant expression of microRNAs (miRNAs) in the cancer stroma is associated with cancer progression remains to be fully elucidated. The aim of the present study was to identify the miRNAs associated with liver metastasis in the cancer stroma of human colorectal cancer (CRC). Using laser capture microdissection, cancer stroma was obtained from the primary lesion of six patients with CRC with liver metastasis (CRCwLM) and six patients with CRC without liver metastasis (CRCwoLM), and miRNA microarray analysis was performed. Candidate miRNA expression status in the stroma was validated by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analysis in 40 CRC cases (wLM, n=20; woLM, n=20), and the association between miRNA expression and clinicopathological factors was assessed in 101 advanced CRC samples. The localization of candidate miRNAs in CRCs was analyzed using in situ hybridization analysis (ISH). The microarray analysis identified six miRNAs with expression differing between the CRCwLM and CRCwoLM cancer stroma. Validation using RT‑qPCR analysis of the stroma showed that the expression levels of miR‑221 and miR‑222 in the cancer stroma were significantly higher in CRCwLM than in CRCwoLM. The RT‑qPCR analysis of 101 CRC samples showed that a high expression level of miR‑221 or miR‑222 in the cancer stroma was associated with liver metastasis, distant metastasis, and shorter overall survival rate of patients with CRC (P<0.05). Increased levels of miR‑221 and miR‑222 were observed in cancer cells and in fibroblasts in the stromal tissue in the ISH analysis. The results suggested that the overexpression of miR‑221 and miR‑222 in the cancer stroma is associated with the metastatic activity and malignant potential in patients with CRC.

Prognostic Role of miR-221 and miR-222 Expression in Cancer Patients: A Systematic Review and Meta-Analysis

“…Then, the entire text of the remaining 362 studies was assessed, determining the removal of 312 further studies. Finally, 50 articles, published between 2009 and 2018, were included in the systematic review [35,36,37,38,39,40,41,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93]. A detailed flow-chart illustrating the literature selection process is presented in Figure 1.…”

“…The main general information on the included studies are reported in Table 1 and Table 2. Among them, 27 focused on miR-221 [36,38,40,52,54,57,60,61,62,64,69,70,72,73,74,75,79,80,81,82,83,84,85,88,89,91,92], 11 on miR-222 [37,39,53,56,59,63,67,68,86,87,93], and the remaining 12 investigated the cluster miR-221/miR-222 [35,41,51,55,58,65,66,71,76,77,78,90]. Overall, 6086 patients suffering from different tumors were included in the systematic review, with the sample size in each study ranging from 20 to 393 patients.…”

MiR‐222 inhibits apoptosis in porcine follicular granulosa cells by targeting the THBS1 gene

“…In cells, miRNAs regulate a variety of important physiological and pathological processes, including cell proliferation (Han, Yin, & Zhang, ), differentiation (Wu et al, ), apoptosis (Yao, Pan, Du, Zhang, & Li, ), and hormone biosynthesis and secretion (Song et al, ). Previous studies have indicated that miR‐222 is an important regulatory factor for cancer development (Galardi et al, ; Gong et al, ; Gu et al, ; Guo et al, ; Huang, Ouyang, Wei, & Yu, ; Iida et al, ; le Sage et al, ; Liu et al, ). In the bovine ovaries, the expression level of miR‐222 was found to be low in preovulatory follicles and high in corpus luteum (Özdemir & Çomaklı, ).…”

Cell‐free microRNAs as early predictors of graft viability during ex vivo normothermic machine perfusion of human donor livers

“…Although not as extensively studied as HDmiR‐122, CDmiR‐222 was shown to be abundantly expressed in biliary epithelium . Elevated levels have been reported in serum of patients with primary sclerosing cholangitis, in tissue of hepatocellular carcinoma and in primary colorectal cancer lesions with liver metastases . CDmiR‐222 was also found to be lower in the preservation solution of grafts that developed NAS after transplantation .…”

“…HDmiR-122, but not CDmiR-222, at 30 min was associated with bicarbonate level in bile at 6 h NMP (D). Spearman's correlation coefficient (r) and P-value are indicated sclerosing cholangitis, in tissue of hepatocellular carcinoma and in primary colorectal cancer lesions with liver metastases [36][37][38]. CDmiR-222…”