Potential of miR-21 to Predict Incomplete Response to Chemoradiotherapy in Rectal Adenocarcinoma

Abstract

Background: Patients with locally advanced rectal adenocarcinoma (LARC) are treated with neoadjuvant chemoradiotherapy (CRT). However, biomarkers for patient selection are lacking, and the association between miRNA expression and treatment response and oncological outcomes is unclear. Objectives: To investigate miRNAs as predictors of response to neoadjuvant CRT and its association with oncological outcomes. Methods: This retrospective study analyzed miRNA expression (miR-16, miR-21, miR-135b, miR-145, and miR-335) in pre-and post-chemoradiation rectal adenocarcinoma tissue and non-neoplastic mucosa in 91 patients treated with neoadjuvant CRT (50.4 Gy) and proctectomy. Two groups were defined: a pathological complete responders group (tumor regression grade-TRG 0) and a pathological incomplete responders group (TRG 1, 2, and 3). Results: miR-21 and miR-135b were upregulated in tumor tissue of incomplete responders comparing with non-neoplastic tissue (p = 0.008 and p < 0.0001, respectively). Multivariate analysis showed significant association between miR-21 in pre-CRT tumor tissue and response, with a 3.67 odds ratio (OR) of incomplete response in patients with higher miR-21 levels (p = 0.04). Although with no significance, patients treated with 5-fluorouracil (5-FU) presented reduced odds of incomplete response compared with those treated with capecitabine (OR = 0.19; 95% confidence interval (CI) 0.03-1.12, p = 0.05). Moreover, significant differences were seen in overall survival (OS) in relation to clinical TNM stage (p = 0.0004), cT (p = 0.0001), presence of distant disease (p = 0.002), mesorectal tumor deposits (p = 0.003), and tumor regression grade (p = 0.04). Conclusion: miR-21 may predict response to CRT in rectal cancer (RC).

The Use of miRNAs in Predicting Response to Neoadjuvant Therapy in Oesophageal Cancer

“…In oesophageal cancer, high miR-21 has been associated with increased stromal fibroblast activity and increased cell migration [ 77 ]; therefore, it is thought to act as an oncogene during the neoplastic life cycle of OSCC with its function being less clear in OAC [ 76 , 78 ]. Studies suggest miR-21 is a useful biomarker in the prediction of response to other cancers such as HER2 positive breast cancer and colorectal cancers [ 79 , 80 ].…”

Development and Validation of a Nomogram and a Comprehensive Prognostic Analysis of an LncRNA-Associated Competitive Endogenous RNA Network Based on Immune-Related Genes for Locally Advanced Rectal Cancer With Neoadjuvant Therapy

“…To explore the mechanisms of hub IRDEGs in response to CRT for LARC, we constructed a ceRNA network (42). miRNAs and lncRNAs are molecules that play important roles in regulating gene expression during normal or pathological cellular processes at the posttranscriptional level (43)(44)(45). In our study, we identified the DEmiRNAs and DElncRNAs between normal and tumor tissues and explored the candidate DEmRNAs based on the IRDEGs.…”

MiR-21 in the Cancers of the Digestive System and Its Potential Role as a Diagnostic, Predictive, and Therapeutic Biomarker

“…Growing evidence suggests the use of miR-21 alone or in combination with other miRNAs in predicting response to chemoradiotherapy (CRT) in CRC [ 105 , 106 , 107 ]. A significant association between miR-21 in pre-neoadjuvant CRT tumor tissue and response, with a 3.67 odds ratio (OR) of incomplete response in patients with higher miR-21 levels ( p = 0.04), has been reported, suggesting the role of miR-21 in predicting an incomplete response to CRT in rectal adenocarcinoma [ 106 ].…”

“…Growing evidence suggests the use of miR-21 alone or in combination with other miRNAs in predicting response to chemoradiotherapy (CRT) in CRC [ 105 , 106 , 107 ]. A significant association between miR-21 in pre-neoadjuvant CRT tumor tissue and response, with a 3.67 odds ratio (OR) of incomplete response in patients with higher miR-21 levels ( p = 0.04), has been reported, suggesting the role of miR-21 in predicting an incomplete response to CRT in rectal adenocarcinoma [ 106 ]. Over-expression of miR-21 has been noted to be associated with 5-FU resistance by targeting and inhibiting the expression of its direct target gene, PDCD4 [ 108 ], and miR-21 has been proposed to be used as an important indicator for 5-FU therapeutic efficacy in CRC [ 109 ].…”