期刊
ENDOCRINE
卷 71, 期 2, 页码 418-426出版社
SPRINGER
DOI: 10.1007/s12020-020-02417-y
关键词
BRAF mutation; Thyroid cancer; Vemurafenib; HMGB1; Autophagy
Thyroid carcinoma, the most common endocrine malignancy, often harbors BRAFV600E mutations. The specific inhibitor vemurafenib has shown great therapeutic advancements, but resistance remains a challenge. This study reveals that HMGB1-mediated autophagy may contribute to vemurafenib resistance in BRAF-mutant thyroid cancer.
Purpose Thyroid carcinoma is the most frequent endocrine malignancy with high occurrence of BRAFV600E mutations. Though targeted therapy by vemurafenib, a specific inhibitor for BRAFV600E, has achieved great advance in therapeutic landscape, resistance occurrence is still a clinical challenge. Here, we sought to elucidate the function of high mobility group box 1 (HMGB1) in vemurafenib resistance in thyroid cancer harboring BRAF mutation. Methods The expression of HMGB1 in BRAF-mutant BCPAP and BRAF-wild CAL-62 cells were determined by qRT-PCR and western. Then, BCPAP cells were transfected with recombinant HMGB1 plasmids, and vemurafenib-resistant BCPAP-R cells were treated with si-HMGB1. The efficacy of HMGB1 on vemurafenib resistance was evaluated by detecting cell viability, apoptosis, and caspase-3 activity. In addition, the involvement of autophagy pathway was investigated. Results Lower expression of HMGB1 was observed in BRAF-mutant BCPAP cells that had high sensitivity to vemurafenib. Overexpression of HMGB1 attenuated BCPAP cell sensitivity to vemurafenib by increasing cell viability and decreasing cell apoptosis and caspase-3 activity. Intriguingly, higher expression of HMGB1 was confirmed in vemurafenib-resistant BCPAP-R cells. Moreover, knockdown of HMGB1 sensitized BCPAP-R cells to vemurafenib resistance. Mechanistically, vemurafenib exposure induced autophagy by enhancing LC3II, Beclin-1 expression, and reducing autophagy substrate p62 expression. Importantly, targeting HMGB1 suppressed vemurafenib-induced autophagy. Blocking autophagy pathway with its inhibitor 3-MA offset BCPAP-R cell resistance to vemurafenib. Conclusions These findings highlight that HMGB1-mediated autophagy may account for vemurafenib resistance in thyroid cancer harboring BRAF mutation, implying a promising approach to overcome vemurafenib resistance in vemurafenib-mutant thyroid carcinomas.
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