Chaperone-mediated autophagy governs progression of papillary thyroid carcinoma via PPARγ-SDF1/CXCR4 signaling.
分子伴侣介导的自噬通过 ppar γ-sdf1/CXCR4 信号调控甲状腺乳头状癌的进展。
- 作者列表："Hong Z","Xin X","Ying C","Yi L","Zhaogen C","Li D","Yijie W","Yongde P","Tang S","Xu H
CONTEXT:Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy. Chaperone-mediated autophagy (CMA), one type of autophagy, has been considered promoting or suppressing cancer development in different cancer types. However, the effect of CMA on PTC development and the underlying mechanisms remained unknown. OBJECTIVE:To determine whether CMA plays implied critical roles in the development of PTC. DESIGN:We investigated the association between CMA and PTC development in PTC tissues and normal thyroid tissues by detecting the key protein of CMA, LAMP2A, using quantitative PCR and immunohistochemistry, which was further validated in the TGCA dataset. The effect of CMA on PTC development was studied by cell proliferation, migration, and apoptosis assays. The underlying mechanisms of PPARγ-SDF1/CXCR4 signaling were clarified by western blotting, quantitative PCR and rescue experiments. Knockdown and tamoxifen were used to analyze the effect of ERα on CMA. RESULTS:Our study confirmed that CMA, indicated by LAMP2A expression, was significantly increased in PTC tumor tissues and cell lines, and was associated with tumor size and lymph node metastasis of patients. Higher CMA in PTC promoted tumor cell proliferation and migration, thereby promoting tumor growth and metastasis. These effects of CMA on PTC were exerted by decreasing PPARγ protein expression to enhance SDF1 and CXCR4 expression. Furthermore, CMA was found positively regulated by ERα signaling in PTC. CONCLUSION:Our investigation identified CMA regulated by ERα promoting PTC tumor progression that enhanced tumor cell proliferation and migration by targeting PPARγ-SDF1/CXCR4 signaling, representing a potential target for treatment of PTC.
背景: 甲状腺乳头状癌 (PTC) 是最常见的内分泌恶性肿瘤。分子伴侣介导的自噬 (CMA) 是自噬的一种类型，一直被认为在不同的癌症类型中促进或抑制癌症的发展。然而，CMA 对 PTC 发育的影响及其潜在机制仍然未知。 目的: 确定 CMA 是否在 PTC 的发展中发挥隐含的关键作用。 设计: 我们通过检测 CMA，LAMP2A 的关键蛋白，使用定量 PCR 和免疫组织化学，研究了 CMA 与 PTC 发育在 PTC 组织和正常甲状腺组织中的相关性,在 TGCA 数据集中进一步验证。通过细胞增殖、迁移和凋亡试验研究 CMA 对 PTC 发育的影响。通过 western blotting 、定量 PCR 和拯救实验阐明了 ppar γ-sdf1/CXCR4 信号的潜在机制。采用敲低和他莫昔芬分析 er α 对 CMA 的影响。 结果: 我们的研究证实，LAMP2A 表达表示的 CMA 在 PTC 肿瘤组织和细胞系中显著增加，并与患者的肿瘤大小和淋巴结转移相关。PTC 中较高的 CMA 促进肿瘤细胞增殖和迁移，从而促进肿瘤生长和转移。CMA 对 PTC 的这些作用是通过降低 ppar γ 蛋白表达来增强 SDF1 和 CXCR4 的表达来发挥的。此外，在 PTC 中发现 CMA 受 er α 信号的正调控。 结论: 我们的研究确定了由 er α 调控的 CMA 促进 PTC 肿瘤进展，通过靶向 ppar γ-sdf1/CXCR4 信号增强肿瘤细胞增殖和迁移，代表了治疗 PTC 的潜在靶点。
METHODS:OBJECTIVES:To assess the prevalence of Hashimoto thyroiditis (HT) in primary thyroid lymphoma (PTL) and whether it differs between mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B-cell lymphoma (DLBCL). METHODS:Electronic databases were searched for studies assessing HT prevalence in PTL, based on antithyroid antibodies, clinical history, or pathology. Pooled prevalence of HT and its association with histotype (MALT or DLBCL) were calculated. RESULTS:Thirty-eight studies with 1,346 PTLs were included. Pooled prevalence results were 78.9% (any HT evidence), 65.3% (antithyroid antibodies), 41.7% (clinical history), and 64% (pathology). HT prevalence was significantly higher in MALT lymphoma than in DLBCL (P = .007) and in mixed DLBCL/MALT than in pure DLBCL (P = .002). CONCLUSIONS:Overall, 78.9% of patients with PTL have any HT evidence, but only half of these had been clinically followed. The difference in HT prevalence suggests that a subset of DLBCL may not derive from MALT lymphoma.
METHODS:Background Whether chronic lymphocytic thyroiditis (CLT) influences the risk of development and the progression of papillary thyroid cancer (PTC) remains uncertain. We investigated the effects of CLT on the clinicopathologic features and prognosis of PTC. Methods Two thousand nine hundred twenty-eight consecutive patients with PTC treated between 2009 and 2017 were divided into two groups: one with chronic lymphocytic thyroiditis and one without; 1174 (40%) of the patients had coincident CLT. Results In univariate analysis, CLT correlated positively with small tumor size, frequent extrathyroidal extension, multifocal diseases, and p53 but negatively with central lymph node (LN) metastasis and BRAF mutation. In multivariate analysis, CLT was associated with extrathyroidal extension and multifocal disease; however, it was not a prognostic factor for recurrence even though it was associated with two aggressive factors. Compared with patients with PTC alone, there were more retrieved central LNs in the PTC + CLT group, and these patients also underwent more invasive diagnostic tests such as fine needle aspiration cytology and frozen biopsy of LN. Conclusions The CLT patients with PTC had better behavior features and prognoses than did those with PTC alone despite frequent multifocality and extrathyroidal extension. However, precaution may be necessary to avoid performing invasive diagnostic procedures for lateral LN metastasis and to manage the patients appropriately.
METHODS::PTPN2 is one of the members of the protein Tyrosine Phosphatases (PTPs) family. To explore the promotive effect of upregulated PTPN2 induced by inflammatory response or oxidative stress on the progression of thyroid cancer. PTPN2 level in thyroid cancer tissues and cell lines was detected. Kaplan-Meier method was applied for evaluating the prognostic value of PTPN2 in thyroid cancer patients. After stimulation of inflammatory response (treatment of IFN-γ and TNF-α), or oxidative stress (treatment of H2O2), protein level of PTPN2 in K1 cells was measured by Western blot. Regulatory effects of PTPN2 on EdU-positive staining and Ki-67 positive cell ratio in K1 cells either with H2O2 stimulation or not were determined. PTPN2 was upregulated in thyroid cancer tissues and cell lines. Its level was higher in metastatic thyroid cancer patients than those of non-metastatic ones. High level of PTPN2 predicted worse prognosis of thyroid cancer. Treatment of either IFN-γ or TNF-α upregulated protein level of PTPN2 in K1 cells. Meanwhile, H2O2 stimulation upregulated PTPN2, which was reversed by NAC administration. With the stimulation of increased doses of H2O2, EdU-positive staining and Ki-67 positive cell ratio were dose-dependently elevated. Silence of PTPN2 attenuated proliferative ability and Ki-67 expression in K1 cells either with H2O2 stimulation or not. Inflammatory response or oxidative stress induces upregulation of PTPN2, thus promoting the progression of thyroid cancer.