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Plasma microRNA-192-5p can predict the response to neoadjuvant chemotherapy and prognosis in esophageal cancer.

ABSTRACT: Esophageal cancer (EC) is the sixth leading cause of cancer-related death worldwide. Recently, neoadjuvant chemotherapy (NAC) before curative surgery has become a standard treatment for clinical stage II or III EC patients. Some EC patients receive a complete response (CR) by NAC; thus, curative surgery may be unnecessary for such patients. MicroRNA levels in plasma have the potential to be a predictor of response to NAC. In the present study, we focused on miR-192-5p, which is highly expressed in EC tissue. The purpose was to investigate the correlations between levels of plasma miR-192-5p and the response to NAC. Furthermore, molecular functions of miR-192-5p associated with chemosensitivity were examined using EC cell lines. The levels of miR-192-5p in plasma before surgery were evaluated in 113 EC patients. Sixty-nine patients received NAC. miR-192-5p levels in the CR group were significantly higher than in the other groups (p = 0.002). The downregulation of miR-192-5p in the EC cell line inhibited sensitivity to cisplatin, and the overexpression of miR-192-5p in the EC cell line promoted sensitivity to cisplatin. miR-192-5p regulated sensitivity to cisplatin by targeting ERCC3 and ERCC4. Plasma miR-192-5p could be used as a predictor of response to chemotherapy and prognosis in EC patients.

SUBMITTER: Furuke H

PROVIDER: S-EPMC10067423 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Plasma microRNA-192-5p can predict the response to neoadjuvant chemotherapy and prognosis in esophageal cancer.

Furuke Hirotaka H Konishi Hirotaka H Arita Tomohiro T Kataoka Satoshi S Shibamoto Jun J Takabatake Kazuya K Takaki Wataru W Shimizu Hiroki H Yamamoto Yusuke Y Komatsu Shuhei S Shiozaki Atsushi A Fujiwara Hitoshi H Otsuji Eigo E

Cancer science 20221226 4

Esophageal cancer (EC) is the sixth leading cause of cancer-related death worldwide. Recently, neoadjuvant chemotherapy (NAC) before curative surgery has become a standard treatment for clinical stage II or III EC patients. Some EC patients receive a complete response (CR) by NAC; thus, curative surgery may be unnecessary for such patients. MicroRNA levels in plasma have the potential to be a predictor of response to NAC. In the present study, we focused on miR-192-5p, which is highly expressed ...[more]

PMID: 36533956

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Project description:BackgroundAccurate evaluation of the response to neoadjuvant chemotherapy (NAC) provides important information about systemic therapies for breast cancer, which implies pharmacological response, prognosis, and guide further therapy. Gene profiles overcome the shortcomings of the relatively limited detection indicators of the classical pathological evaluation criteria and the subjectivity of observation, but are complicated and expensive. Therefore, it is essential to develop a more accurate, repeatable, and economical evaluation approach for neoadjuvant chemotherapy responses.MethodsWe analyzed the transcriptional profiles of chemo-resistant breast cancer cell lines and tumors of chemo-resistant breast cancer patients in the GSE25066 dataset. We preliminarily screened out common significantly differentially expressed genes and constructed a NAC response risk model using LASSO regression and univariate and multivariate analyses. The differences in bioinformatic features of tumor cells, immune characteristics, and prognosis were compared between high and low-risk group. The potential drugs that could reverse chemotherapy resistance in breast cancer were screened by the CMap database.ResultsThirty-six genes were commonly up/down-regulated in both NAC chemo-resistant tumors and cells compared to the sensitive tumors and wild-type cells. Through LASSO regression, we obtained a risk model composed of 12 genes. The risk model divided patients into high and low-risk groups. Univariate and multivariate Cox regression analyses suggested that the risk score is an independent prognostic factor for evaluating NAC response in breast cancer. Tumors in risk groups exhibited significant differences in molecular biological characteristics, tumor-infiltrating lymphocytes, and immunosuppressive molecule expression. Our results suggested that the risk score was also a good prognostic factor for breast cancer. Finally, we screened potential drugs that could reverse chemotherapy resistance in breast cancer.ConclusionA novel 12 gene-signature could be used to predict NAC response and predict prognosis in breast cancer.

Project description:Early detection of acute kidney injury is difficult due to lack of known biomarkers; previous studies have tried to identify new biomarkers for detecting acute kidney injury at an early stage. MicroRNA, a 21-23 nucleotide noncoding RNA molecule, has emerged as a desirable marker in the diagnosis and prognosis of various diseases. This study aims to identify the expression profile of microRNA in ischemia-reperfusion-induced kidney injury and determine the possibility of using the candidate microRNA as biomarker for the detection of I/R-induced kidney injury. Based on the established rat model of I/R-induced kidney injury, a microarray analysis of rat urine was performed at the beginning of operation (0 h) as well as 72 h post operation. To validate the results, urine samples from 71 patients who underwent cardiac surgery were collected, after which urinalysis was conducted to determine the microRNA concentration. An alternative expression profile of microRNAs was detected in rat urine. The quantitative validation of microRNA showed that the expression of miR-30c-5p, miR-192-5p, and miR-378a-3p was elevated significantly in urine post operation, which was consistent with those of the microarray analysis and earlier than kidney injury molecule-1 (KIM-1). In patients with acute kidney injury, increased levels of miR-30c-5p and miR-192-5p were also detected 2 h post operation, and miR-30c-5p showed preferable diagnostic value compared with protein-based biomarkers. In conclusion, an aberrant expression profile of microRNA was detected in rat urine based on the established ischemia-reperfusion animal model. Both miR-30c-5p and miR-192-5p served as important potential diagnostic markers for I/R-induced kidney injury. Impact statement Firstly, one differentiating factor in our study is that the candidate miRNAs were screened in a controlled animal model rather than in patients with acute kidney injury (AKI) to ensure the purity of the cause of disease and to avoid possible effects of comorbidities on the spectrum of urine miRNA. This ensured the presence of only the relevant candidate miRNA (that associated with I/R injury); and what's more, the alterative expression of miR-192-5p and miR-30c-5p in animal model, patients with AKI, and cell model was confirmed simultaneously, which is likely to be more convincing. Secondly, the candidate miRNAs were screened sequentially at regular time points, which covered the initiation, progression, and partial repair stages, thus ensuring that no significant miRNAs were omitted in the screening process, and miR-biomarkers in 2 h post operation showed preferable diagnostic performance.

Project description:Current treatment for patients with locally advanced esophageal adenocarcinoma (EAC) is neoadjuvant chemotherapy (nCT), alone or combined with radiotherapy, before surgery. However, fewer than 30% of treated patients show a pathologic complete response to nCT, which correlates with increased 5-year survival compared with nonresponders. Understanding the mechanisms of response to nCT is pivotal to better stratify patients and inform more efficacious therapies. Here, we investigated the immune mechanisms involved in nCT response by multidimensional profiling of pretreatment tumor biopsies and blood from 68 patients with EAC (34 prospectively and 34 retrospectively collected), comparing complete responders versus nonresponders to nCT. At the tumor level, complete response to nCT was associated with molecular signatures of immune response and proliferation, increased putative antitumor tissue-resident memory CD39+ CD103+ CD8+ T cells, and reduced immunosuppressive T regulatory cells (Treg) and M2-like macrophages. Systemically, complete responders showed higher frequencies of immunostimulatory CD14+ CD11c+ HLA-DRhigh cells, and reduced programmed cell death ligand 1-positive (PD-L1+) monocytic myeloid-derived suppressor cells, along with high plasma GM-CSF (proinflammatory) and low IL4, CXCL10, C3a, and C5a (suppressive). Plasma proinflammatory and suppressive cytokines correlated directly and inversely, respectively, with the frequency of tumor-infiltrating CD39+ CD103+ CD8+ T cells. These results suggest that preexisting immunity in baseline tumor drives the clinical activity of nCT in locally advanced EAC. Furthermore, it may be possible to stratify patients based on predictive immune signatures, enabling tailored neoadjuvant and/or adjuvant regimens.SignificanceMultidimensional profiling of pretreatment esophageal adenocarcinoma shows patient response to nCT is correlated with active preexisting immunity and indicates molecular pathways of resistance that may be targeted to improve clinical outcomes.

Dataset Information

Plasma microRNA-192-5p can predict the response to neoadjuvant chemotherapy and prognosis in esophageal cancer.

Publications

Plasma microRNA-192-5p can predict the response to neoadjuvant chemotherapy and prognosis in esophageal cancer.

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