Abstract
BackgroundNeoadjuvant chemotherapy (NAC) has become the standard of care for resectable esophageal squamous cell carcinoma (ESCC) which is one of the most lethal cancers, to improve resectability and prognosis. On this basis, to provide individually optimized therapy for ESCC, a minimally-invasive biomarker for response to NAC is strongly desired. This study aimed to identify the miRNA signature in serum specimens taken from ESCC patients undergoing NAC through genome-wide microarray technology.MethodsComprehensive miRNA-expression profiles of serum specimens from ESCC patients before initial treatment were analyzed using microarray. A qPCR assay was performed to test the robustness of identified serum-based miRNA signature for discriminating response to NAC with serum specimens taken from 100 ESCC cases undergoing NAC.ResultsWe prioritized 62 miRNAs differentially expressed between responders and non-responders (absolute log2 fold change > 1.0, corresponding P < 0.05) and from the 62 miRNAs, we selected the miR-23a-5p, miR-193b-5p, and miR-873-3p, which were highly expressed in non-responders. Following qPCR analysis indicated the expression of miR-193b-5p and miR-873-3p in serum specimens were significantly higher in non-responders among three selected miRNAs (P = 0.004 and 0.001, respectively). Subsequently, we developed 2-miR-model (miR-193b-5p and miR-873-3p), 3-miR-model, and 2-miR + lymphatic invasion (ly) model based on logistic regression analysis, which achieved the better area under the receiver operating characteristic curves than those of single miRNAs as 2-miR-model, 0.70 (95% CI 0.57 to 0.82); 3-miR-model, 0.70 (95% CI 0.57 to 0.83); and 2-miR + ly, 0.73 (95% CI 0.60–0.86), respectively. Furthermore, we compared the detective power of the combined model: 2-miR + ly for discriminating non-responders to NAC, to other pretreatment clinical features. Consequently, 2-miR + ly model was superior to serum SCC antigen with great significance (P = 0.01) and to ly, and clinical T stage with marginal significance (P = 0.18, 0.07, respectively).ConclusionsCollectively, we demonstrated that the potential of a multi-miRNA biomarker for identifying NAC response in ESCC is realistic, and can be used in the clinic with the further validation.
Highlights
Neoadjuvant chemotherapy (NAC) has become the standard of care for resectable esophageal squamous cell carcinoma (ESCC) which is one of the most lethal cancers, to improve resectability and prognosis
Identification of micro RNA (miRNA) signature for NAC response of ESCC using a microarray‐based miRNA expression profiling To develop a miRNA signature for prediction of NAC response of ESCC, we first interrogated a microarraybased miRNA expression profiling results in pre-treatment serum specimens of eight ESCC patients treated with NAC consisting of cisplatin plus 5FU or S-1
QPCR verification with serum specimens taken from ESCC patients treated with NAC Using serum specimens taken from 100 ESCC patients prior to initial treatment, we performed quantitative PCR (qPCR) assay of three selected miRNAs
Summary
Neoadjuvant chemotherapy (NAC) has become the standard of care for resectable esophageal squamous cell carcinoma (ESCC) which is one of the most lethal cancers, to improve resectability and prognosis. On this basis, to provide individually optimized therapy for ESCC, a minimally-invasive biomarker for response to NAC is strongly desired. The mature form of miRNA is short nucleotide molecules as 21–25 base pairs and miRNA is capable of inhibiting transcription by inducing degradation of the target mRNAs [10] Due to their high stability both in the cell and in extracellular body fluids such as blood, urine, and saliva, miRNAs are attractive candidates for minimally-invasive biomarker of various diseases including ESCC [11,12,13]. The functional roles of miRNAs in tumor biology are incredibly complicated and all the functions have not been fully discovered, we expect that circulating blood miRNA could predict clinical behavior of ESCC including drug sensitivity
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