Affiliations: [a] Liaoning Laboratory of Cancer Genetics and Epigenetics and Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China | [b] Department of Orthopedic Surgery, The Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, China
Correspondence:
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Corresponding authors: Pei-Nan Li, Department of Orthopedic Surgery, The Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning 116011, China. E-mail: [email protected]. Jia Liu, Liaoning Laboratory of Cancer Genetics and Epigenetics and Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, China. E-mail: [email protected].
Abstract: BACKGROUNDS: Anaplastic thyroid cancer/ATC is highly lethal malignancy without reliable chemotherapeutic drug. Resveratrol possesses anti-ATC activities but encounters resistance in some cases due to certain unknown reason(s). OBJECTIVE: Because signal transducer and activator of transcription/STAT3 signaling is critical for ATC cell survival and the main molecular target of resveratrol, its roles in determining the fates of resveratrol-treated ATC cells were investigated here. METHODS: Human THJ-11T, THJ-16 and THJ-21T ATC cell lines were treated by 100 μM resveratrol and their growth, statuses of STAT3 signaling and STAT3-related gene expression were examined. The relevance of STAT3 activation with resveratrol resistance was elucidated using STAT selective inhibitor AG490. Leukemia inhibitory factor/LIF expression and phosphorylated-STAT3/p-STAT3 nuclear translocation in ATC tissues were immunohistochemically analyzed. RESULTS: Resveratrol inhibited proliferation, p-STAT3 nuclear translocation as well as LIF and STAT3 expression of THJ-16T and THJ-21T but not THJ-21T cells which showed LIF upregulation and more frequent p-STAT3 nuclear translocation. AG490 significantly prevent p-STAT3 nuclear translocation, and reversed the resveratrol tolerance of THJ-11T cells. Immonohistochemical staining revealed 14.3% (4/28) of LIF and 3.6% (1/28) of p-STAT3 detection in noncancerous ATC-surrounding tissues, which increased to 89.5% (17/19) and 52.6% (10/19) respectively among ATC specimens. The correlative analysis indicated the relevance of LIF expression and STAT3 activation (r= 0.825; P< 0.01). CONCLUSIONS: The status of STAT3 activation and LIF expression are closely correlated with the therapeutic effect of resveratrol on ATCs. Frequent LIF upregulation and STAT3 activation are the unfavorable factors of ATCs and the potential targets of anti-ATC therapy.
Keywords: Anaplastic thyroid cancer, STAT3 signaling, resveratrol, drug resistance
