南方医科大学学报 ›› 2025, Vol. 45 ›› Issue (11): 2416-2426.doi: 10.12122/j.issn.1673-4254.2025.11.14
姜雪凝1(
), 黄晴晴2, 徐盈2, 王舜印2, 张小凤2, 王炼1, 王月月2, 左芦根1,2(
)
收稿日期:2025-05-06
出版日期:2025-11-20
发布日期:2025-11-28
通讯作者:
左芦根
E-mail:jiangxn1202@163.com;zuolugen@126.com
作者简介:姜雪凝,在读硕士研究生,E-mail: jiangxn1202@163.com
基金资助:
Xuening JIANG1(
), Qingqing HUANG2, Ying XU2, Shunyin² WANG2, Xiaofeng² ZHANG2, Lian¹ WANG1, Yueyue² WANG2, Lugen ZUO1,2(
)
Received:2025-05-06
Online:2025-11-20
Published:2025-11-28
Contact:
Lugen ZUO
E-mail:jiangxn1202@163.com;zuolugen@126.com
Supported by:摘要:
目的 探究YEATS2在胃癌组织中的表达水平及其临床预后价值,并揭示其对胃癌细胞EMT进程的作用和机制。 方法 基于TIMER2.0、GEPIA等公共数据库预测YEATS2在胃癌中的表达水平;纳入100例在本院接受胃癌根治术的患者,通过免疫组化检测胃癌及癌旁组织中YEATS2表达,分析其与临床病理参数和Ki67的相关性;采用Kaplan-Meier生存分析、Cox回归和ROC曲线评估YEATS2的预后价值;通过生物富集分析预测YEATS2对胃癌可能的作用和机制,构建YEATS2敲低与过表达的胃癌细胞系(HGC-27与AGS),设shNC、shYEATS2、Vector和OE-YEATS2组,分别采用shRNA阴性对照慢病毒和YEATS2特异性干扰慢病毒、空载对照慢病毒载体及YEATS2过表达慢病毒进行转染。结合细胞划痕、Transwell和Western blotting检测YEATS2对胃癌细胞迁移、侵袭及EMT的作用。 结果 YEATS2在胃癌组织中表达显著高于癌旁组织且与Ki67表达呈正相关(P<0.05)。YEATS2高表达组中CEA≥5 μg/L、CA19-9≥37 kU/L、T3-4期及N2-3期的患者比例高于低表达组(P<0.05)。生存分析显示YEATS2高表达患者术后5年生存率降低(P<0.001),ROC曲线分析表明YEATS2评估胃癌患者根治术后5年生存率的敏感性为80.00%,特异性为66.67%(P<0.05)。Cox回归显示YEATS2高表达是胃癌患者术后5年生存率低的独立危险因素(HR:1.675,95%CI:1.013~2.771,P=0.045)。富集分析提示YEATS2可能与胃癌EMT过程和Wnt/β-catenin通路有关。体外实验表明,YEATS2高表达可促进胃癌细胞迁移、侵袭,同时上调Vimentin、N-cadherin、Wnt和Active β-catenin,并下调E-cadherin的表达(P<0.05)。经XAV-939(Wnt/β-catenin抑制剂)处理后,YEATS2过表达导致的EMT相关蛋白表达变化(N-cadherin、Vimentin上调和E-cadherin下调)被显著削弱(P<0.05)。 结论 YEATS2高表达可能激活Wnt/β-catenin通路促进胃癌细胞EMT进程,并与患者预后不良有关。
姜雪凝, 黄晴晴, 徐盈, 王舜印, 张小凤, 王炼, 王月月, 左芦根. 高表达YEATS2通过激活Wnt/β-catenin通路促进胃癌细胞上皮-间质转化进程[J]. 南方医科大学学报, 2025, 45(11): 2416-2426.
Xuening JIANG, Qingqing HUANG, Ying XU, Shunyin² WANG, Xiaofeng² ZHANG, Lian¹ WANG, Yueyue² WANG, Lugen ZUO. High YEATS2 expression promotes epithelial-mesenchymal transition in gastric cancer cells by activating the Wnt/β-catenin signaling pathway[J]. Journal of Southern Medical University, 2025, 45(11): 2416-2426.
图1 胃癌组织中YEATS2和Ki67的表达及相关性分析
Fig.1 Expression and correlation analysis of YEATS2 and Ki67 in gastric cancer. A: Expression of YEATS2 in different human tumors. B: Expression of YEATS2 in gastric cancer. C: Immunohistochemical staining of YEATS2 and Ki67. D,E: Relative IOD values of YEATS2 and Ki67. F: Correlation between YEATS2 and Ki67 in gastric cancer tissues. *P<0.05,***P<0.001 vs adjacent tissue.
图2 YEATS2高表达与胃癌患者肿瘤分级和分期相关
Fig.2 High YEATS2 expression is significantly associated with tumor grading and staging in gastric cancer patients. A: Correlation between YEATS2 TPM and tumor grading in gastric cancer. B: Correlation between YEATS2 TPM and tumor staging in gastric cancer. ***P<0.001 vs adjacent tissue.
| Factor | n | YEATS2 expression | χ2 | P | ||
|---|---|---|---|---|---|---|
| Low (n=50) | High (n=50) | |||||
| Gender | Female | 19 | 6 (31.58%) | 13 (68.42%) | 3.184 | 0.074 |
| Male | 81 | 44 (54.32%) | 37 (45.68%) | |||
| Age (year) | ˂60 | 35 | 18 (51.43%) | 17 (48.57%) | 0.044 | 0.834 |
| ≥60 | 65 | 32 (49.23%) | 33 (50.77%) | |||
| Cancer cell type | Adenocarcinoma | 79 | 42 (53.16%) | 37 (46.84%) | 1.507 | 0.220 |
| Other | 21 | 8 (38.10%) | 13 (61.90%) | |||
| CEA (μg/L) | ˂5 | 35 | 24 (68.57%) | 11 (31.43%) | 7.429 | 0.006 |
| ≥5 | 65 | 26 (40.00%) | 39 (60.00%) | |||
| CA19-9 (kU/L) | ˂37 | 44 | 27 (61.36%) | 17 (38.64%) | 4.058 | 0.044 |
| ≥37 | 56 | 23 (41.07%) | 33 (58.93%) | |||
| Tumor size (cm) | ˂5 | 49 | 27 (55.10%) | 22 (44.90%) | 1.000 | 0.317 |
| ≥5 | 51 | 23 (45.10%) | 28 (54.90%) | |||
| T stage | T1-T2 | 36 | 25 (69.44%) | 11 (30.56%) | 8.507 | 0.004 |
| T3-T4 | 64 | 25 (39.06%) | 39 (60.94%) | |||
| N stage | N0-N1 | 43 | 27 (62.79%) | 16 (37.21%) | 4.937 | 0.026 |
| N2-N3 | 57 | 23 (40.35%) | 34 (59.65%) | |||
表1 胃癌组织中YEATS2表达水平与胃癌恶性进展参数间的关系
Tab.1 Relationship between YEATS2 expression level and parameters of malignant progression in gastric cancer tissues (n=50)
| Factor | n | YEATS2 expression | χ2 | P | ||
|---|---|---|---|---|---|---|
| Low (n=50) | High (n=50) | |||||
| Gender | Female | 19 | 6 (31.58%) | 13 (68.42%) | 3.184 | 0.074 |
| Male | 81 | 44 (54.32%) | 37 (45.68%) | |||
| Age (year) | ˂60 | 35 | 18 (51.43%) | 17 (48.57%) | 0.044 | 0.834 |
| ≥60 | 65 | 32 (49.23%) | 33 (50.77%) | |||
| Cancer cell type | Adenocarcinoma | 79 | 42 (53.16%) | 37 (46.84%) | 1.507 | 0.220 |
| Other | 21 | 8 (38.10%) | 13 (61.90%) | |||
| CEA (μg/L) | ˂5 | 35 | 24 (68.57%) | 11 (31.43%) | 7.429 | 0.006 |
| ≥5 | 65 | 26 (40.00%) | 39 (60.00%) | |||
| CA19-9 (kU/L) | ˂37 | 44 | 27 (61.36%) | 17 (38.64%) | 4.058 | 0.044 |
| ≥37 | 56 | 23 (41.07%) | 33 (58.93%) | |||
| Tumor size (cm) | ˂5 | 49 | 27 (55.10%) | 22 (44.90%) | 1.000 | 0.317 |
| ≥5 | 51 | 23 (45.10%) | 28 (54.90%) | |||
| T stage | T1-T2 | 36 | 25 (69.44%) | 11 (30.56%) | 8.507 | 0.004 |
| T3-T4 | 64 | 25 (39.06%) | 39 (60.94%) | |||
| N stage | N0-N1 | 43 | 27 (62.79%) | 16 (37.21%) | 4.937 | 0.026 |
| N2-N3 | 57 | 23 (40.35%) | 34 (59.65%) | |||
图3 YEATS2对胃癌患者预后的影响
Fig.3 Effect of YEATS2 on prognosis of patients with gastric cancer. A: Kaplan-Meier analysis. B: Survival curves. C: Predictive value of YEATS2 for 5-year survival after radical gastrectomy.
| Factor | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|
| Log-rank χ2 | P | HR | 95% CI | P | ||
| Gender (male vs female) | <0.001 | 0.989 | ||||
| Age (˂60 years vs ≥60 years ) | 0.014 | 0.907 | ||||
| Cancer cell type (adenocarcinoma vs other) | 0.539 | 0.463 | ||||
| CEA (˂5 μg/L vs ≥5 μg/L) | 24.128 | <0.001 | 2.760 | 1.480-5.147 | 0.001 | |
| CA19-9 (˂37kU/L vs ≥37 kU/L) | 30.316 | <0.001 | 2.600 | 1.480-4.569 | <0.001 | |
| Tumor size (˂5 cm vs ≥5 cm) | 1.041 | 0.308 | ||||
| T stage (T1-T2 vs T3-T4) | 15.477 | <0.001 | 2.015 | 1.129-3.593 | 0.018 | |
| N stage (N0-N1 vs N2-N3) | 25.115 | <0.001 | 2.238 | 1.275-3.928 | 0.005 | |
| YEATS2 expression (high vs low) | 13.939 | <0.001 | 1.675 | 1.013-2.771 | 0.045 | |
表2 胃癌患者术后5年生存期的影响因素分析
Tab.2 Analysis of risk factors affecting 5-year survival rate of gastric cancer patients after radical gastrectomy
| Factor | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|
| Log-rank χ2 | P | HR | 95% CI | P | ||
| Gender (male vs female) | <0.001 | 0.989 | ||||
| Age (˂60 years vs ≥60 years ) | 0.014 | 0.907 | ||||
| Cancer cell type (adenocarcinoma vs other) | 0.539 | 0.463 | ||||
| CEA (˂5 μg/L vs ≥5 μg/L) | 24.128 | <0.001 | 2.760 | 1.480-5.147 | 0.001 | |
| CA19-9 (˂37kU/L vs ≥37 kU/L) | 30.316 | <0.001 | 2.600 | 1.480-4.569 | <0.001 | |
| Tumor size (˂5 cm vs ≥5 cm) | 1.041 | 0.308 | ||||
| T stage (T1-T2 vs T3-T4) | 15.477 | <0.001 | 2.015 | 1.129-3.593 | 0.018 | |
| N stage (N0-N1 vs N2-N3) | 25.115 | <0.001 | 2.238 | 1.275-3.928 | 0.005 | |
| YEATS2 expression (high vs low) | 13.939 | <0.001 | 1.675 | 1.013-2.771 | 0.045 | |
图5 YEATS2促进胃癌细胞的迁移
Fig.5 YEATS2 promotes migration of gastric cancer cells. A-D: Validation of YEATS2 knockdown and overexpression in gastric cancer cells. E, F: High expression of YEATS2 promotes HGC-27 cell migration. G, H: High expression of YEATS2 promotes AGS cell migration. n=3, *P<0.05 vs shNC or vs Vector.
图6 YEATS2促进胃癌细胞的迁移和侵袭
Fig.6 YEATS2 promotes migration and invasion of gastric cancer cells. A-D: High expression of YEATS2 promotes HGC-27 cell migration and invasion. E-H: High expression of YEATS2 promotes AGS cell migration and invasion. n=3, *P<0.05 vs shNC or vs Vector.
图7 YEATS2促进胃癌细胞的EMT进程
Fig.7 YEATS2 promotes EMT process in gastric cancer cells. A, B : Expressions of key EMT-related proteins in HGC27 cells. C, D: Expressions of key EMT-related proteins in AGS cells. n=3, *P<0.05 vs shNC or vs Vector.
图8 胃癌中YEATS2的表达升高激活Wnt/β-catenin信号通路
Fig.8 Elevated expression of YEATS2 in gastric cancer cells activates the Wnt/β-catenin signaling pathway. A, B: Expressions of Wnt, active β-catenin and c-myc in HGC-27 cells. C, D: Expressions of Wnt, active β-catenin and c-myc in AGS cells. E: Expressions of key EMT-related proteins in HGC27 cells. F: Expressions of key EMT-related proteins in AGS cells. n=3, *P<0.05 vs shNC or vs Vector or vs OE-YEATS2.
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