Abstract
Papillary thyroid cancer can dedifferentiate into a much more aggressive form of thyroid cancer, namely into anaplastic thyroid cancer. Nrf2 is commonly activated in papillary thyroid cancer, whereas its role in anaplastic thyroid cancer has not been fully explored. In this study, we used two cell lines and an animal model to examine the function of Nrf2 in anaplastic thyroid cancer. The role of Nrf2 in anaplastic thyroid cancer was investigated by a series of functional studies in two anaplastic thyroid cancer cell lines, FRO and KAT-18, and further confirmed with an in vivo study. The impact of Nrf2 on the sensitivity of anaplastic thyroid cancer cells to lenvatinib was also investigated to evaluate its potential clinical implication. We found that the expression of Nrf2 was significantly higher in anaplastic thyroid cancer cell line cells than in papillary thyroid cancer cells or normal control cells. Knockdown of Nrf2 in anaplastic thyroid cancer cells inhibited their viability and clonogenicity, reduced their migration and invasion ability in vitro, and suppressed their tumorigenicity in vivo. Mechanistically, knockdown of Nrf2 decreased the expression of Notch1. Lastly, knockdown of Nrf2 increased the sensitivity of anaplastic thyroid cancer cells to lenvatinib. As knockdown of Nrf2 reduced the metastatic and invasive ability of anaplastic thyroid cancer cells by inhibiting the Notch 1 signaling pathway and increased the cancer cell sensitivity to lenvatinib, Nrf2 could be a promising therapeutic target for patients with anaplastic thyroid cancer.
Highlights
Anaplastic thyroid cancer (ATC) is an aggressive form of thyroid cancer representing approximately 1% of thyroid cancers [1, 2]
Two differentiated thyroid cancer (DTC) cell lines, BCPAP and WRO, two ATC cell lines, FRO and KAT-18, and a normal control cell line Nthy-ori-3.1 were maintained in DMEM (Gibco, Life Technologies) medium supplemented with 10% (v/v) heat-inactivated fetal bovine serum (FBS, Gibco, Life Technologies)
To explore the clinical implications of Nrf2 on ATC cells, we evaluated the impact of Nrf2 on the effect of lenvatinib that has been used to treat patients with ATC
Summary
Anaplastic thyroid cancer (ATC) is an aggressive form of thyroid cancer representing approximately 1% of thyroid cancers [1, 2]. ATC patients usually do not meet surgical treatment criteria at diagnosis and do not respond to chemotherapy or targeted therapies. It accounts for the majority of thyroid cancer deaths [3]. The median overall survival for ATC is only 4 months from time of diagnosis, and its disease-specific mortality is almost 100% [4]. This dire situation indicates that the development of new treatment strategies for ATC is urgently needed. Nuclear factor erythroid-derived 2-like 2 (NFE2L2), known as Nrf, is a transcription
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