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Endocrine

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01-02-2021 | Thyroid Cancer | Original Article

Involvement of HMGB1 in vemurafenib resistance in thyroid cancer cells harboring BRAF (V600E) mutation by regulating excessive autophagy

Authors: Lin Run, Liping Wang, Xiting Nong, Nan Li, Xin Huang, Yang Xiao

Published in: Endocrine | Issue 2/2021

Abstract

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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Title: Involvement of HMGB1 in vemurafenib resistance in thyroid cancer cells harboring BRAF (V600E) mutation by regulating excessive autophagy
Authors: Lin Run
Liping Wang
Xiting Nong
Nan Li
Xin Huang
Yang Xiao
Publication date: 01-02-2021
Publisher: Springer US
Keywords: Thyroid Cancer
Thyroid Cancer
Thyroid Cancer
Published in: Endocrine / Issue 2/2021
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI: https://doi.org/10.1007/s12020-020-02417-y

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Abstract

Purpose

Methods

Results

Conclusions

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