Overexpression of miRNA 4451 is Associated With a Poor Survival of Patients With Hypopharyngeal Cancer After Surgery With Postoperative Radiotherapy

Abstract

Hypopharyngeal cancer (HC) is the most common subset of head and neck cancers. These tumors often have an aggressive clinical outcome characterized by local invasion and regional nodal metastasis. Upregulated miRNAs might be useful as biomarkers for prognosis and molecular targets for these tumors. We determined tumor expression of candidate miRNAs using microarray in 8 HC patients and validated in 372 HC patients. We also used paired tumorous and mucosal tissue to verify the miRNA expression. Log-rank test and Cox model were used to evaluate the survival; and Harrell's C-index was used to compare concordance of Cox models. Our results indicated 7 miRNAs aberrantly expressed in HC. Three of these candidate miRNAs (miRNA-4415, miRNA-200a, and miRNA-30b) were selected for further qRT-PCR validation and all of them were frequently found upregulated in HC tumors; with miR-4451 being the most differentially expressed. Moreover, high expression of miR-4451 was positively correlated with advanced tumor stage and increased mortality risk (HR: 1.6, 95% CI: 1.2–2.3; adjusted HR: 1.5, adjusted 95% CI: 1.1–2.1). Finally, significantly higher expression of miR-4451 in tumors compared to in fresh adjacent normal tissues indicates an oncogenic role of miR-4451 in this tumor. Upregulated miR-4451 in HC samples were frequently found and is significantly associated with advanced stage and poor survival of HC, which may indicate an association of this miRNA with the carcinogenesis process in this tumor site; and they could serve as a prognostic biomarker as well as help develop potential new targets for therapy.

A 3‐miRNA signature predicts survival of patients with hypopharyngeal squamous cell carcinoma after post‐operative radiotherapy

“…A total of 73 patients (19.6%) were non‐smokers, and 96 patients (25.8%) have no history of alcohol drinking in discovery cohort, whereas there were 24 non‐smokers (17.3%) and 35 non‐drinkers (25.2%) in validation cohort. Similarly to our previous report, in both cohort there were no significant associations between OS and epidemiological/clinical variables, such as age, sex, smoking and drinking status except the T and N stage, having a high grade of T (T4) or N (N2/N3) with a worse prognosis …”

“…As shown in Table , the univariate analysis showed that the patients with high expression of miR‐200a‐3p and miR‐30b‐5p had approximately 1.5‐ to 1.6‐fold increased risk of overall death and 1.7‐ to 1.8‐fold increased risk of death owing to the disease compared with the patients with corresponding low expression, respectively (For OS: cHR, 1.5; 95% CI, 1.1‐2.9 for miR‐200a‐3p and 1.6; 95% CI, 1.1‐2.2 for miR‐30b‐5p; for DSS: cHR, 1.8; 95% CI, 1.3‐2.6 for miR‐200a‐3p and 1.7; 95% CI, 1.2‐2.5 for miR‐30b‐5p). Similarly, the patients with high expression of miR‐4451 had approximately 1.6‐fold increased risk of overall death (cHR, 1.6; 95% CI, 1.1‐2.2) compared with those with its low expression as we previously reported . The risk of death owing to the disease was 70% higher in patients with high expression of miR‐4451 (cHR, 1.7; 95% CI, 1.2‐2.4) than those with the corresponding low expression.…”

“…Similarly, the patients with high expression of miR-4451 had approximately 1.6-fold increased risk of overall death (cHR, 1.6; 95% CI, 1.1-2.2) compared with those with its low expression as we previously reported 12. The risk of death owing to the disease was 70% higher in patients with high expression of miR-4451 (cHR, 1.7; 95% CI, 1.2-2.4) than those with the corresponding low expression.…”

“…Unlike miR‐200a‐3p and miR‐30b‐5p, which were widely studied in different cancers, miR‐4451 was identified more recently, for which few studies were focused on its function or mechanisms in human cancer development and prognosis. Our previous study showed miR‐4451 was highly expressed in patients with HSCC, and high expression of miR‐4451 was associated with a shorter survival of patient with HSCC, while the molecular mechanisms behind the association of miR‐4451 high expression with worse survival need more in‐depth studies.…”

“…After high‐throughput screening by microarray, the candidate miRNAs were verified by qRT‐PCR analysis. As previously described, the 100 ng of total RNA of each sample was polyadenylated and reversely transcripted to cDNA. Then, a quantified PCR was carried out in the Qiagen miScript system (Qiagen) on the ABI 7900HT platform (ABI).…”