载脂蛋白C1高表达通过激活JAK2/STAT3信号通路促进甲状腺乳头状癌细胞的增殖并抑制凋亡

doi:10.12122/j.issn.1673-4254.2025.02.17

摘要/Abstract

摘要：

目的探讨载脂蛋白C1（APOC1）在甲状腺乳头状癌（PTC）组织中的表达及对PTC细胞增殖、凋亡及关键信号通路的影响。方法通过GEPIA 2及K-M数据库分析APOC1在PTC的表达及对预后的影响。采用免疫组织化学、Western blotting检测APOC1在PTC和癌旁组织中的表达以及3株PTC细胞和正常甲状腺Nthyori 3-1细胞的表达。采用细胞转染技术，构建APOC1敲低和过表达PTC细胞模型（TPC-1细胞和BCPAP细胞）；采用Western blotting和RT-qPCR分别在蛋白水平和mRNA水平检验细胞模型构建是否成功。通过生长曲线、集落形成实验检测敲低和过表达APOC1后细胞的生长情况和集落形成能力；通过流式细胞术检测敲低和过表达APOC1对细胞周期、凋亡的影响。采用RT-qPCR和Western blotting检测增殖及凋亡相关靶基因P21，P27，CDK4，CyclinD1，BCL-2，Bax，caspase-3/caspase-9 mRNA和蛋白以及JAK2/STAT3信号通路关键蛋白的变化。结果成功构建APOC1敲低和过表达PTC细胞模型；PTC组织及3个PTC细胞株APOC1表达高于癌旁组织和Nthyori 3-1细胞（P<0.001）。与对照组相比，沉默组细胞增殖能力减弱（P<0.05）；G0/G1期的细胞比例增高（P<0.01），S和G2期的细胞比例下降（P<0.05）；细胞凋亡率明显增高（P<0.05）；CDK4，CyclinD1，BCL-2 mRNA和蛋白表达量下调（P<0.05）；p-JAK2，p-STAT3蛋白表达下调（P<0.001）；增强组与沉默组结果相反：P21，P27，Bax，caspase-3/caspase-9 mRNA和蛋白表达下调（P<0.05）；p-JAK2，p-STAT3蛋白表达上调（P<0.001）。JAK2抑制剂AG490显著减弱过表达APOC1对BCPAP细胞JAK2/STAT3信号通路的激活效应（P<0.01）。结论 APOC1可能通过激活JAK2/STAT3信号通路，缩短G0/G1期进程，促进PTC细胞增殖并抑制凋亡。

关键词: 甲状腺乳头状癌, 载脂蛋白C1, 增殖, 凋亡, JAK2/STAT3信号通路

Abstract:

Objective To investigate the expression of apolipoprotein C1 (APOC1) in papillary thyroid carcinoma (PTC) and its effects on proliferation and apoptosis of PTC cells. Methods The expression level of APOC1 in PTC and its impact on prognosis were analyzed using GEPIA 2 and Kaplan-Meier databases. Immunohistochemistry (IHC) and Western blotting were used to detect the expression of APOC1 in PTC and adjacent tissues and in 3 PTC cell lines and normal thyroid Nthyori 3-1 cells. In TPC-1 and BCPAP cells, the effect of Lipofectamine 2000-mediated transfection with APOC1 siRNA or an APOC1-overexpressing plasmid on cell growth and colony formation ability were examined by observing the growth curves and using colony-forming assay. The changes in cell cycle and apoptosis of the transfected cells were analyzed with flow cytometry. RT-qPCR and Western blotting were used to detect the changes in expressions of P21, P27, CDK4, cyclin D1, Bcl-2, Bax, caspase-3 and caspase-9 and the key proteins in the JAK2/STAT3 signaling pathway. Results APOC1 expression was significantly higher in PTC tissues and the 3 PTC cell lines than in the adjacent tissues and Nthyori 3-1 cells, respectively. In TPC-1 and BCPAP cells, APOC1 knockdown obviously reduced cell proliferative activity, increased the percentage of G0/G1 phase cells, lowered the percentages of S and G2 phase cells, promoted cell apoptosis, and downregulated mRNA and protein expression levels of CDK4, cyclin D1 and Bcl-2 and the protein levels of p-JAK2 and p-STAT3. APOC1 overexpression in the cells produced the opposite effects on cell proliferation, apoptosis, cell cycle and the mRNA and protein expressions. The application of AG490, a JAK2 inhibitor, strongly attenuated APOC1 overexpression-induced activation of the JAK2/STAT3 signaling pathway in BCPAP cells. Conclusion APOC1 overexpression promotes proliferation and inhibits apoptosis of PTC cells possibly by activating the JAK2/STAT3 signaling pathway and accelerating cell cycle progression.

Key words: papillary thyroid carcinoma, apolipoprotein C1, proliferation, apoptosis, JAK2/STAT3 signaling pathway

宾禹, 李子雯, 左素微, 孙思诺, 李敏, 宋佳茵, 林旭, 薛刚, 吴靖芳. 载脂蛋白C1高表达通过激活JAK2/STAT3信号通路促进甲状腺乳头状癌细胞的增殖并抑制凋亡[J]. 南方医科大学学报, 2025, 45(2): 359-370.

Yu BIN, Ziwen LI, Suwei ZUO, Sinuo SUN, Min LI, Jiayin SONG, Xu LIN, Gang XUE, Jingfang WU. High expression of apolipoprotein C1 promotes proliferation and inhibits apoptosis of papillary thyroid carcinoma cells by activating the JAK2/STAT3 signaling pathway[J]. Journal of Southern Medical University, 2025, 45(2): 359-370.

图/表 14

表1 引物序列

Tab.1 Primer sequences for RT-qPCR

Gene	Sequence
APOC1	F:5'-CTGGTGGTGGTTCTGTCGAT-3'
	R:5'-TCACTCTGTTTGATGCGGCT-3'
β-actin	F:5'-CCTGGGCATGGAGTCCTGTG-3'
	R:5'-AGGGGCCGGACTCGTCATAC-3'

图1 生物信息学网站分析APOC1在患者PTC组织及Adjacent组织的表达

Fig.1 Bioinformatic analysis of APOC1 expression in PTC and Adjacent tissues. A: Analysis of expression levels of APOC1 in PTC tissues and adjacent tissues using GEPIA 2 database (*P<0.05). B, C: Analysis of the relationship between APOC1 mRNA expression and patient prognosis using Kaplan-Meier database.

图2 APOC1在PTC及癌旁组织中的表达

Fig.2 Expression of APOC1 in clinical samples of PTC and adjacent tissues. A: Western blotting for detecting APOC1 expression in PTC tissues and adjacent tissues. B: Quantitative analysis of expression level. ***P<0.001 vs adjacent tissue.

图3 APOC1在PTC及癌旁组织中的表达

Fig.3 Immunohistochemical detection of APOC1 expression in PTC and Adjacent tissue. A: APOC1 positive signal in PTC tissue (brown) in the cytoplasm. B: Negative expression of APOC1 in adjacent tissue.

图4 ICC结果显示APOC1表达量TPC-1>K1>BCPAP> Nthyori 3-1

Fig.4 Immunocytochemical detection of APOC1 protein in TPC-1, K1, BCPAP and Nthyori 3-1 cells. A: Negative expression of APOC1 in normal thyiod follicular epithelial Nthyori 3-1 cells. B-D: Positive signals of APOC1 in the 3 PTC cell lines located in the cytoplasm.

图5 APOC1在K1, TPC-1, BCPAP及Nthyori 3-1中的表达

Fig.5 Western blotting and RT-qPCR for detecting APOC1 expression in K1, TPC-1, BCPAP and Nthyori 3-1 cells. A,B: Expression levels of APOC1 protein in different cell lines detected by Western blotting. C: Expression levels of APOC1 mRNA in different cell lines. ***P<0.001, ****P<0.0001 vs Nthyori 3-1 cells (n=3).

图6 沉默对照组及不同沉默组中APOC1蛋白及mRNA的表达水平

Fig.6 Expression of APOC1 protein and mRNA in TPC-1 cells with APOC1 knockdown. A,B: Expression levels of APOC1 protein in TPC-1 cells with APOC1 knockdown detected by Western blotting. C: Expression levels of APOC1 mRNA in TPC-1 cells with APOC1 knockdown. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs shRNAC (n=3).

图 7 TPC-1细胞沉默APOC1后的蛋白及mRNA表达含量

Fig.7 Decreased APOC1 expressions at both protein and mRNA levels in TPC-1 cells with APOC1 knockdown. A, B: Expression levels of APOC1 protein in shRNAC group, shRNA1 group, and shRNA2 group. C: Expression levels of APOC1 mRNA in the shRNAC group, shRNA1 group, and shRNA2 group. *P<0.05, **P<0.01, ***P<0.001 vs shRNAC (n=3).

图8 BCPAP细胞增强APOC1后的蛋白及mRNA表达含量

Fig.8 Increased APOC1 protein and mRNA levels in BCPAP cells with APOC1 overexpression. A, B: Expression levels of APOC1 protein in OENC and OE groups. C: Expression levels of APOC1 mRNA in OENC and OE groups. **P<0.01, ****P<0.0001 vs OENC (n=3).

图9 沉默及增强APOC1对细胞增殖的影响

Fig.9 Effect of APOC1 knockdown and overexpresison on PTC cell proliferation. A, C: Colony formation assay of the transfected cells. B,D: Number of cell clusters in the transfected cells. E,G: Growth curves of the transfected cells. F,H: Cell confluence of the transfected cells. *P<0.05,**P<0.01,***P<0.001, ****P<0.001 vs shRNAC/OENC (n=3).

图10 沉默及增强APOC1对细胞周期的影响

Fig.10 Effect of APOC1 knockdown and overexpresison on cell cycle. A, C: Cell cycle diagrams of the cells with APOC1 knockdown and overexpresison. B, D: Analysis of cell cycle percentage. *P<0.05, **P<0.01, ***P<0.001 vs shRNAC/OENC (n=3).

图11 沉默及增强APOC1对细胞凋亡的影响

Fig.11 Effect of APOC1 knockdown and overexpresison on cell apoptosis. A,C: Cell apoptosis maps of cells with APOC1 knockdown and overexpresison. B,D: Percentages of apoptotic cells each group.**P<0.01, ***P<0.001 vs shRNAC/OENC (n=3).

图12 沉默及增强APOC1对周期、凋亡蛋白及mRNA的影响

Fig.12 Effect of APOC1 knockdown and overexpresison on expresisons of cell cycle and apoptosis-related proteins and their mRNA levels. A-C: Cell cycle-related protein and mRNA expression levels of in cells with APOC1 knockdown. D-F: Cell cycle-related protein and mRNA expression levels in APOC1 knockdown group. G-I: Apoptosis-related protein and mRNA expression levels in APOC1 overexpression group. J-L: Apoptosis-related protein and mRNA expression levels in APOC1 knockdown group. *P<0.05, **P<0.01,***P<0.001, ****P<0.0001 vs shRNAC/OENC (n=3).

图13 APOC1的表达对JAK2/STAT3信号通路的影响

Fig.13 APOC1 knockdown and overexpresison on expressions of key proteins in the JAK2/STAT3 signaling pathway detected by Western blotting. A,B: Expression levels of key proteins in the JAK2/STAT3 signaling pathway in APOC1 knockdown group. C,D: Expression levels of key proteins in the JAK2/STAT3 signaling pathway in APOC1 overexpression group. **P<0.01, ***P<0.001, ****P<0.0001 vs shRNAC/OENC (n=3).

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