Neoadjuvant chemotherapy followed by surgery has been recommended for esophageal cancer (EC) patients. Though improved survival is obtained in patients with pathological complete response after multimodal therapy, still many patients do not respond to the therapy and show increased therapy induced complications. Therefore, identifying non-responders before starting the treatment is warranted to avoid unnecessary drug exposure. So far, no reliable biomarkers are available for prediction of response to neoadjuvant therapy in EC patients. We hypothesized that differential miRNA profiles may be exhibited by the EC patients who respond to neoadjuvant therapy versus non-responders. The present study aims to identify differentially expressed (DE) miRNAs that might have potential as biomarkers for predicting response to neoadjuvant therapy in EC.
Next generation sequencing (NGS) was performed to compare miRNA profiles of EC patients who respond to neoadjuvant therapy versus non-responder. Identification of targets of DE miRNAs followed by Ingenuity Pathway Analysis (IPA) was carried out to identify enriched pathways. Further, expression of 2 downregulated miRNAs, miR-335 and miR-107 and one upregulated miRNA, miR-99a was evaluated by qRT-PCR in clinical samples and their association with response was assessed. Next, we modulated the expression of miR-335 in esophageal cancer cell lines and its effect on EMT and PI3K signalling and cisplatin resistance was assessed.
Out of 76 significantly DE miRNAs, 21 miRNAs were upregulated and 55 were down regulated. Ingenuity Pathway analysis indicated the significant enrichment of Xenobiotic metabolism, EMT signalling and PI3K/AKT signalling pathways in responders. Further, ectopic expression of miR-335 in EC cells led to decrease in EMT and PI3K signalling as well as resistance towards cisplatin in these cells.
The present study suggests association of miR-335, miR-107 and miR-99a with response to therapy in EC patients, however validation in larger cohorts is warranted.
The authors.
Indian Council of Medical Research, Govt. of India.
All authors have declared no conflicts of interest.