甲状腺癌中调节性细胞死亡机制的研究进展

doi:10.16139/j.1007-9610.2025.06.12

摘要/Abstract

摘要：

甲状腺癌是目前发病率增长较快的恶性肿瘤之一。部分难治性病人面临着药物毒性及耐药挑战，急需找到新的治疗通路机制以改善预后。调节性细胞死亡（RCD）是一种基因高度调控的有序死亡模式，包括凋亡、坏死性凋亡、焦亡、铁死亡和铜死亡等，近年来研究发现RCD与肿瘤进展侵袭、耐药性高度相关。本文系统综述甲状腺癌中各类死亡模式，包括各死亡通路的核心信号节点，并探讨其在肿瘤进展中具体涉及的功能，总结靶向各死亡通路的潜在治疗策略。然而，RCD机制的复杂性及治疗灵敏性仍存争议，未来需聚焦筛选广谱靶点、开发协同疗法，最终实现基于细胞死亡的精准治疗，改善难治性甲状腺癌预后。

关键词: 甲状腺癌, 调节性细胞死亡, 靶向治疗, 耐药机制, 联合疗法

Abstract:

Thyroid carcinoma is one of the malignant tumors with rapidly increasing incidence rates. Some refractory patients face challenges from drug toxicity and resistance, urgently requiring the discovery of new therapeutic pathways to improve prognosis. Regulatory cell death（RCD）is a highly regulated orderly death mode, including apoptosis, necroptosis, pyroptosis, ferroptosis, and cuproptosis. Recent studies have found that RCD is closely associated with tumor progression, invasion, and resistance. This article systematically reviewed various death modes in thyroid cancer, including the core signaling nodes of each death pathway, and explored their specific functions in tumor progression. It also summarized potential therapeutic strategies targeting these death pathways. However, the complexity of RCD mechanisms and the sensitivity of treatments remain controversial. Future efforts should focus on screening broad-spectrum targets and developing synergistic therapies to ultimately achieve precise treatment based on cell death, thereby improving the prognosis of refractory thyroid cancer.

Key words: Thyroid carcinoma, Regulated cell death(RCD), Targeted therapy, Drug resistance mechanism, Combination therapy

中图分类号:

R736.1

牛灵珊, 赵越, 施旭, 杨哲宇, 潘睿俊, 蔡伟. 甲状腺癌中调节性细胞死亡机制的研究进展[J]. 外科理论与实践, 2025, 30(06): 529-536.

NIU Lingshan, ZHAO Yue, SHI Xu, YANG Zheyu, PAN Ruijun, CAI Wei. Research progress on the mechanism of regulated cell death in thyroid carcinoma[J]. Journal of Surgery Concepts & Practice, 2025, 30(06): 529-536.

图/表 1

参考文献 46

[1]	BRAY F, LAVERSANNE M, SUNG H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74(3):229-263.
[2]	HAN B, ZHENG R, ZENG H, et al. Cancer incidence and mortality in China, 2022[J]. J Natl Cancer Cent, 2024, 4(1):47-53.
[3]	CHEN D W, LANG B H H, MCLEOD D S A, et al. Thyroid cancer[J]. Lancet, 2023, 401(10387):1531-1544. doi: 10.1016/S0140-6736(23)00020-X pmid: 37023783
[4]	SUBBIAH V, HU M I, WIRTH L J, et al. Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study[J]. Lancet Diabetes Endocrinol, 2021, 9(8):491-501. doi: 10.1016/S2213-8587(21)00120-0 URL
[5]	WIRTH L J, SHERMAN E, ROBINSON B, et al. Efficacy of selpercatinib in RET-altered thyroid cancers[J]. N Engl J Med, 2020, 383(9):825-835. doi: 10.1056/NEJMoa2005651 URL
[6]	TANG D, KANG R, BERGHE T V, et al. The molecular machinery of regulated cell death[J]. Cell Res, 2019, 29(5):347-364. doi: 10.1038/s41422-019-0164-5 pmid: 30948788
[7]	LIU J, KUANG F, KROEMER G, et al. Autophagy-dependent ferroptosis: machinery and regulation[J]. Cell Chem Biol, 2020, 27(4):420-435. doi: S2451-9456(20)30069-6 pmid: 32160513
[8]	CZABOTAR P E, LESSENE G, STRASSER A, et al. Control of apoptosis by the BCL-2 protein family[J]. Nat Rev Mol Cell Biol, 2014, 15(1):49-63. doi: 10.1038/nrm3722
[9]	TABAS I, RON D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress[J]. Nat Cell Biol, 2011, 13(3):184-190. doi: 10.1038/ncb0311-184 pmid: 21364565
[10]	HETZ C, ZHANG K, KAUFMAN R J. Mechanisms, regulation and functions of the unfolded protein response[J]. Nat Rev Mol Cell Biol, 2020, 21(8):421-438. doi: 10.1038/s41580-020-0250-z
[11]	KISCHKEL F C, HELLBARDT S, BEHRMANN I, et al. Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor[J]. EMBO J, 1995, 14(22):5579-5588. doi: 10.1002/j.1460-2075.1995.tb00245.x pmid: 8521815
[12]	LI H, ZHU H, XU C J, et al. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis[J]. Cell, 1998, 94(4):491-501. doi: 10.1016/s0092-8674(00)81590-1 pmid: 9727492
[13]	SOMNAY Y R, YU X M, LLOYD R V, et al. Notch3 expression correlates with thyroid cancer differentiation, induces apoptosis, and predicts disease prognosis[J]. Cancer, 2017, 123(5):769-782. doi: 10.1002/cncr.30403 pmid: 27861750
[14]	XIONG H, YU J, JIA G, et al. Emerging roles of circUBAP2 targeting miR-370-3p in proliferation, apoptosis, and invasion of papillary thyroid cancer cells[J]. Hum Cell, 2021, 34(6):1866-1877. doi: 10.1007/s13577-021-00585-1 pmid: 34346032
[15]	FU S, ZHAO N, JING G, et al. Matrine induces papillary thyroid cancer cell apoptosis in vitro and suppresses tumor growth in vivo by downregulating miR-182-5p[J]. Biomed Pharmacother, 2020, 128:110327. doi: 10.1016/j.biopha.2020.110327 URL
[16]	GUNDA V, SAROSIEK K A, BRAUNER E, et al. Inhibition of MAPKinase pathway sensitizes thyroid cancer cells to ABT-737 induced apoptosis[J]. Cancer Lett, 2017, 395:1-10. doi: S0304-3835(17)30145-3 pmid: 28259821
[17]	STUCKEY D W, SHAH K. TRAIL on trial: preclinical advances in cancer therapy[J]. Trends Mol Med, 2013, 19(11):685-694. doi: 10.1016/j.molmed.2013.08.007 pmid: 24076237
[18]	FULDA S, VUCIC D. Targeting IAP proteins for therapeutic intervention in cancer[J]. Nat Rev Drug Discov, 2012, 11(2):109-124. doi: 10.1038/nrd3627 pmid: 22293567
[19]	WEST A C, JOHNSTONE R W. New and emerging HDAC inhibitors for cancer treatment[J]. J Clin Invest, 2014, 124(1):30-39. doi: 10.1172/JCI69738 pmid: 24382387
[20]	TORTI S V, TORTI F M. Iron and cancer: more ore to be mined[J]. Nat Rev Cancer, 2013, 13(5):342-355. doi: 10.1038/nrc3495 pmid: 23594855
[21]	JIANG L, KON N, LI T, et al. Ferroptosis as a p53-mediated activity during tumour suppression[J]. Nature, 2015, 520(7545):57-62. doi: 10.1038/nature14344
[22]	SUN X, OU Z, CHEN R, et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells[J]. Hepatology, 2016, 63(1):173-184. doi: 10.1002/hep.28251 pmid: 26403645
[23]	WANG H H, MA J N, ZHAN X R. Circular RNA circ_0067934 attenuates ferroptosis of thyroid cancer cells by miR-545-3p/SLC7A11 signaling[J]. Front Endocrinol (Lausanne), 2021, 12:670031. doi: 10.3389/fendo.2021.670031 URL
[24]	SIRAJ A K, PARVATHAREDDY S K, PRATHEESHKUMAR P, et al. PD-L1 is an independent prognostic marker in middle eastern PTC and its expression is upregulated by BRAFV600E mutation[J]. Cancers (Basel), 2021, 13(3):555. doi: 10.3390/cancers13030555 URL
[25]	董佳悦, 李树杰, 王艳, 等. 双氢青蒿素和索拉非尼诱导未分化甲状腺癌铁死亡的协同机制[J]. 中华内分泌代谢杂志, 2023, 39(7):596-604.
	DONG J Y, LI S J, WANG Y, et al. Synergistic mechanism of dihydroartemisinin and sorafenib in inducing ferroptosis in undifferentiated thyroid carcinoma[J]. Chin J Endocrinol Metabolism, 2023, 39(7):596-604.
[26]	RENAUD C O, ZIROS P G, CHARTOUMPEKIS D V, et al. Keap1/Nrf2 signaling: a new player in thyroid pathophysiology and thyroid cancer[J]. Front Endocrinol (Lausanne), 2019, 10:510. doi: 10.3389/fendo.2019.00510 URL
[27]	CHEN H, LI Z, XU J, et al. Curcumin induces ferroptosis in follicular thyroid cancer by upregulating HO-1 expression[J]. Oxid Med Cell Longev, 2023, 2023:6896790.
[28]	WANG X, XU S, ZHANG L, et al. Vitamin C induces ferroptosis in anaplastic thyroid cancer cells by ferritinophagy activation[J]. Biochem Biophys Res Commun, 2021, 551:46-53. doi: 10.1016/j.bbrc.2021.02.126 URL
[29]	GUO Y, LIANG J, DING L, et al. The endoplasmic reticulum stress-ferroptosis reciprocal signaling orchestrates anti-tumor effect of anlotinib in anaplastic thyroid cancer[J]. Cancer Cell Int, 2025, 25(1):310. doi: 10.1186/s12935-025-03947-z
[30]	JIANG M, QI L, LI L, et al. The caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer[J]. Cell Death Discov, 2020, 6:112. doi: 10.1038/s41420-020-00349-0 pmid: 33133646
[31]	LI F, DU R, KOU J, et al. Elucidating the role of pyroptosis in papillary thyroid cancer: prognostic, immunological, and therapeutic perspectives[J]. Cancer Cell Int, 2024, 24(1):45. doi: 10.1186/s12935-024-03229-0 pmid: 38287330
[32]	ZHAO Q, FENG H, YANG Z, et al. The central role of a two-way positive feedback pathway in molecular targeted therapies-mediated pyroptosis in anaplastic thyroid cancer[J]. Clin Transl Med, 2022, 12(2):e727. doi: 10.1002/ctm2.727 pmid: 35184413
[33]	ZHANG L, JIANG Y H, FAN C, et al. MCC950 attenuates doxorubicin-induced myocardial injury in vivo and in vitro by inhibiting NLRP3-mediated pyroptosis[J]. Biomed Pharmacother, 2021, 143:112133. doi: 10.1016/j.biopha.2021.112133 URL
[34]	BOURNE C M, TAABAZUING C Y. Harnessing pyroptosis for cancer immunotherapy[J]. Cells, 2024, 13(4):346. doi: 10.3390/cells13040346 URL
[35]	CHEN L, MIN J, WANG F. Copper homeostasis and cuproptosis in health and disease[J]. Signal Transduct Target Ther, 2022, 7(1):378.
[36]	SHI Y, SHENG P, GUO M, et al. Cuproptosis-related lncRNAs predict prognosis and immune response of thyroid carcinoma[J]. Front Genet, 2023, 14:1100909. doi: 10.3389/fgene.2023.1100909 URL
[37]	HUANG J, SHI J, WU P, et al. Identification of a novel cuproptosis-related gene signature and integrative analyses in thyroid cancer[J]. J Clin Med, 2023, 12(5):2014. doi: 10.3390/jcm12052014 URL
[38]	CHEN Y G, LIU H X, HONG Y, et al. PCNP is a novel regulator of proliferation, migration, and invasion in human thyroid cancer[J]. Int J Biol Sci, 2022, 18(9):3605-3620. doi: 10.7150/ijbs.70394 URL
[39]	YANG Z, HUANG R, WEI X, et al. The SIRT6-autophagy-warburg effect axis in papillary thyroid cancer[J]. Front Oncol, 2020, 10:1265. doi: 10.3389/fonc.2020.01265 pmid: 32983963
[40]	WU J, LIANG J, LIU R, et al. Autophagic blockade potentiates anlotinib-mediated ferroptosis in anaplastic thyroid cancer[J]. Endocr Relat Cancer, 2023, 30(9):e230036.
[41]	WANG W, KANG H, ZHAO Y, et al. Targeting autophagy sensitizes BRAF-mutant thyroid cancer to vemurafenib[J]. J Clin Endocrinol Metab, 2017, 102(2):634-643. doi: 10.1210/jc.2016-1999 pmid: 27754804
[42]	WANG Z, WU P, SHI J, et al. A novel necroptosis-related gene signature associated with immune landscape for predicting the prognosis of papillary thyroid cancer[J]. Front Genet, 2022, 13:947216. doi: 10.3389/fgene.2022.947216 URL
[43]	LI Y, WU D. Identification of signature genes and immune infiltration analysis in thyroid cancer based on PANoptosis related genes[J]. Front Endocrinol (Lausanne), 2024, 15:1397794. doi: 10.3389/fendo.2024.1397794 URL
[44]	XIE D, HUANG L, LI C, et al. Identification of PANoptosis-related genes as prognostic indicators of thyroid cancer[J]. Heliyon, 2024, 10(11):e31707. doi: 10.1016/j.heliyon.2024.e31707 URL
[45]	GUO Y W, ZHU L, DUAN Y T, et al. Ruxolitinib induces apoptosis and pyroptosis of anaplastic thyroid cancer via the transcriptional inhibition of DRP1-mediated mitochondrial fission[J]. Cell Death Dis, 2024, 15(2):125. doi: 10.1038/s41419-024-06511-1
[46]	BROECKER-PREUSS M, VIEHOF J, JASTROW H, et al. Cell death induction by the BH3 mimetic GX15-070 in thyroid carcinoma cells[J]. J Exp Clin Cancer Res, 2015, 34(1):69. doi: 10.1186/s13046-015-0186-x URL