Hsa_circ_0011290 regulates proliferation, apoptosis and glycolytic phenotype in papillary thyroid cancer via miR-1252/ FSTL1 signal pathway.
Hsa_circ_0011290 通过 miR-1252/ FSTL1 信号通路调控甲状腺乳头状癌的增殖、凋亡和糖酵解表型。
- 作者列表："Hu Z","Zhao P","Zhang K","Zang L","Liao H","Ma W
OBJECTIVE:Despite of previous report regarding the aberrant overexpression of hsa_circ_0011290 in thyroid cancer, the regulatory mechanism and mechanistic involvements of which were still elusive currently in papillary thyroid cancer (PTC). Here we set out to characterize expression status and functional contributions of hsa_circ_0011290 in this disease especially through mode-of-action of sponging RNA. METHODS:Relative expression of hsa_circ_0011290, microRNA (miR)-1252 and FSTL1 was quantified by real-time polymerase chain reaction. Glucose metabolism was determined by examination of glucose uptake, lactate production and ATP contents. The regulatory effects of miR-1252 on both hsa_circ_0011290 and Follistatin Like 1 (FSTL1) were interrogated by luciferase reporter assay. Direct binding between miR-1252 with hsa_circ_0011290 and FSTL1 transcripts were analyzed by RNA pulldown assay. Protein levels of FSTL1 was examined by Western blots. RESULTS:Aberrant over-expression of hsa_circ_0011290 was associated with advanced stage and unfavorable prognosis of PTC. Knockdown of hsa_circ_0011290 greatly inhibited cell viability, proliferation and stimulated cell apoptosis in PTC cells. Meanwhile, glucose metabolism was significantly switched with decreased glucose uptake and lactate production, and increased ATP contents. We identified miR-1252 as target miR of hsa_circ_0011290, and miR-1252 evidently inhibited expressions of both luciferase reporter and endogenous hsa_circ_0011290, and miR-1252 was negatively regulated by hsa_circ_0011290 vice versa. We further suggested that FSTL1 as direct target of miR-1252, and provided direct evidences in support of binding between miR-1252 with both hsa_circ_0011290 and FSTL1. Through sponging miR-1252, hsa_circ_0011290 was capable of positively modulate FSTL1 expression. Notably, inhibition of miR-1252 completely reversed phenotypic effects of hsa_circ_0011290 knockdown including cell viability, proliferation, apoptosis and glucose metabolisms. CONCLUSION:Our study uncovered the oncogenic contributions of hsa_circ_0011290-miR-1252-FSTL1 in PTCs.
目的: 尽管之前有关于 hsa_circ_0011290 在甲状腺癌中异常过表达的报道，但其调控机制和机制参与目前在甲状腺乳头状癌 (PTC) 中仍然难以捉摸。在这里，我们开始表征 hsa_circ_0011290 在这种疾病中的表达状态和功能贡献，特别是通过海绵 RNA 的作用模式。 方法: 通过实时聚合酶链反应定量 hsa_circ_0011290 、 microRNA (miR)-1252 和 FSTL1 的相对表达量。通过检测葡萄糖摄取、乳酸生成和 ATP 含量来测定葡萄糖代谢。通过荧光素酶报告基因检测检测 miR-1252 对 hsa_circ_0011290 和卵泡抑素样 1 (FSTL1) 的调节作用。通过 RNA 下拉分析 hsa_circ_0011290 和 FSTL1 转录本的 miR-1252 之间的直接结合。通过 Western blots 检测 FSTL1 的蛋白水平。 结果: hsa_circ_0011290 的异常高表达与 PTC 的晚期和不良预后相关。敲除 hsa_circ_0011290 大大抑制了 PTC 细胞的细胞活力、增殖和刺激细胞凋亡。同时，葡萄糖代谢显著改变，葡萄糖摄取和乳酸生成减少，ATP 含量增加。我们确定 miR-1252 是 hsa_circ_0011290 的靶 miR，miR-1252 明显抑制荧光素酶报告基因和内源性 hsa_circ_0011290 的表达，反之 miR-1252 受 hsa_circ_0011290 的负调控。我们进一步建议 FSTL1 作为 miR-1252 的直接靶点，并提供直接证据支持 hsa_circ_0011290 和 FSTL1 与 miR-1252 之间的结合。通过海绵 miR-1252，hsa_circ_0011290 能够正向调节 FSTL1 的表达。值得注意的是，抑制 miR-1252 完全逆转了 hsa_circ_0011290 敲除的表型效应，包括细胞活力、增殖、凋亡和葡萄糖代谢。 结论: 我们的研究揭示了 hsa_circ_0011290-miR-1252-FSTL1 在 PTCs 中的致癌作用。
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.