| Thyroid cancer is the most common form of endocrine carcinoma and its incidence is rapidly growing worldwide.Well-differentiated thyroid carcinomas are usually curable by the combined effects of surgery,radioiodide ablation and thyroid stimulating hormone(TSH)suppressive therapy.However,treating advanced thyroid cancer which is recurrent,metastatic and 131 I-refractory,or medullary thyroid cancer,remains a therapeutic challenge.These tumors can not benefit from subsequent 131 I treatment,known as radioiodide refractory differentiated thyroid cancer(RAIR-DTC).There is still lack of effective therapeutic methods to treat these patients bearing RAIR-DTC.Usually,RAIR-DTC progresses quickly and has poor prognosis.The existence of radioresistant cells is one of the major obstacles in radiotherapy.The outcome of RAIR-DTC after repeated 131 I treatment or treatment with increased dosage of 131 I still remains poor.Severe side effects,including pneumonia or pulmonary fibrosis,salivary gland damage and bone marrow suppression,often occur.Despite all advances in the study of the re-differentiation treatment strategy for thyroid carcinoma,the clinical application is still restricted by many factors.Therefore,it is significant to study the molecular mechanism of radioiodide resistance of thyroid tumors,and to find out the methods or drugs that can effectively improve the therapy efficacy of 131 I treatment.In chapter 1,we first introduced the histopathological classification and molecular pathology of thyroid cancer.The common gene variants of thyroid cancer,including BRAF and RAS mutations,RET/PTC and PAX8/PPAR? rearrangements,were briefly described.The pathological mechanisms of RAIR-DTC and the corresponding therapeutic strategies were also summarized.Secondly,the subtypes of autophagy and the different stages of autophagy were introduced.The relationship between autophagy and tumor progression as well as the role of autophagy in sensitizing malignant tumors to radio-or chemo-therapy were discussed.In addition,we summarized the anti-tumor activity of curcumin and its multiple targeting pharmacological properties.Progresses in the study of curcumin as a sensitizing agent for radio-and chemo-therapy were also mentioned.Moreover,the potential targets of curcumin in sensitizing thyroid tumors to radioiodide therapy were proposed.This overview provided some foreshadowing for the following studies.In chapter 2,the radiation sensitization effects of curcumin,a naturally occurring anti-tumor agent,by targeting autophagy were investigated.Curcumin selectively induced autophagic cell death in thyroid cancer cells but not normal cells.It induced autophagic cell death through Akt/mTOR/p70S6K and ERK1/2 signaling pathways.The basal levels of autophagy in thyroid cancer cells and patient-derived tissues were relatively low.Activation of the mTOR signaling pathways has been observed in the tissues from thyroid cancer patients.Further study indicated that curcumin induced mitophagy of thyroid cancer cells,leading to excessive mitochondria clearance.Combined curcumin treatment sensitized thyroid cancer cells to radioiodide via autophagic cell death.The detailed mechanism of curcumin-induced mitophagy was further investigated.Curcumin selectively accumulated in the mitochondria of thyroid cancer cells.In mitochondira,curcumin bonded with the C subunit of succinate dehydrogenase(SDH),also known as mitochondrial respiratory chain complex ?.Then a rapid ROS burst was produced by modulation of mitochondrial succinate dehydrogenase activity.Excessive ROS production triggered mitophagy upon mitochondrial dysfunction.In chapter 3,the effects of curcumin on the differentiation and radioiodide uptake of thyroid cancer cells were investigated.Curcumin restored the expression of sodium iodide symporter(NIS)and enhanced the membrane trafficking of NIS.Correspondingly,the ability of radioiodide uptake by thyroid cancer cells significantly increased.Curcumin promoted the redifferentiation of thyroid cancer cells by inhibiting PI3K-AKT-mTOR signaling pathway.By the way,curcumin restored thyroid-specific gene expression in an autophagy-independent manner.In chapter 4,we explored the impacts of inflammatory microenvironment of thyroid cancer on radioiodide therapy.Serum levels of IL-6 and IL-8 in benign and malignant thyroid lesions were determined by ELISA.Proinflammatory cytokines,IL-6 and IL-8 are highly expressed in thyroid cancer.Data obtained from GEO database(GSE33630)showed that the relative mRNA expression levels of IL-8 and IL-6 were elevated in thyroid cancer,which further confirmed our clinical observations.GRP78 and CHOP,two endoplasmic reticulum(ER)stress markers,are highly expressed in thyroid cancer too.Both of the two ER-stress activators,thapsigargin and tunicamycin,could dose-and time-dependently upregulate the expression of IL-6 and IL-8 in thyroid cancer cells.Hypoxia or starvation conditions,which classically trigger ER-stress,had the similar effects on the expression of IL-6 and IL-8.Morover,rIL-6 and rIL-8 promotes the dedifferentiation of thyroid cancer cells and lowered its ability of radioiodide uptake.Of note,these cytokines could also promote the dedifferentiation of normal thyroid cells through paracrine mechanisms.Previous studies about radioresistant mainly focused on the gene variants of thyroid cancer itself and investigated the effects of gene mutations on iodine-metabolism associated proteins.In the present study,we paid our attention to the inflammatory microenvironment of tumors stimulated by ER stress which could contribute to the resistance of thyroid tumor cells to radioiodine therapy.We found out that curcumin could inhibited ER stress-induced expression of IL-8 and IL-6 in thyroid cancer cells,which indicated that the regulation function of curcumin in the inflammatory microenvironment of tumors may also contribute to its radiation sensitization effects.Moreover,sorafenib,a multikinase inhibitor,was the first drug approved by FDA for the treatment of differentiated thyroid cancer.Our study found out that sorafenib inhibited ER stress-induced expression of IL-8 and IL-6 in thyroid cancer cells.Besides,sorafenib suppressed the basal expression of IL-6 and IL-8 in thyroid cancer cells.These results indicated that sorafenib could not only inhibit tumor angiogenesis but also modulate the inflammatory microenvironment of tumors.Our study provided the experimental basis for the intervention of inflammatory cytokines in the microenvironment to control the carcinogenic factors at the tumor initial stage.In summary,our work discovered and confirmed that curcumin induced excessive mitophagy and led to the autophagic cell death of thyroid cancer cells.It also promoted the redifferentiation and radio iodide uptake of thyroid cancer cells.These functions contribute to the radiation sensitization effects of curcumin.Meanwhile,we found that inflammatory microenvironment induced by ER stress contributed to the radioiodide resistance of thyroid cancer cells.Both curcumin and sorafenib could ameliorate radio iodide resistance through ER stress inhibition.Our study provided a new therapeutic target for thyroid tumors refractory to radio iodide therapy. |
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