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Abstract Thyroid cancer keeps rapidly increasing worldwide and the most frequent type is papillary thyroid carcinoma (PTC). MicroRNAs (miRNAs) are proved dysregulated in many types of malignancies, including thyroid cancer. Although miR-let-7e has been implicated in several types of cancer regulation, relatively little is known about the function of miR-let-7e in PTC. In this study, we showed that the overexpression of miR-let-7e or knockdown of high mobility group box 1 (HMGB1) inhibited cell migration and invasion. MiR-let-7e downregulates HMGB1 expression by directly targeting the HMGB1 3′-UTR. Furthermore, HMGB1 reintroduction reversed the anti-proliferation, anti-migration, and anti-invasion roles of miR-let-7e. miR-let-7e might function as a tumor suppressor in papillary thyroid carcinoma through HMGB1. Therefore, our study demonstrates that miR-let-7e plays an important role in papillary thyroid carcinoma progression and might represent a new potential therapeutic target for treatment. [ABSTRACT FROM AUTHOR]