Expression of TACC3 and its relationship with epithelial mesenchymal transformation in gastric adenocarcinoma
-
摘要:
目的 探讨转录相关酸性卷曲蛋白3(TACC3)在胃腺癌(GAC)中的表达及其与临床病理学参数间的关系,并研究TACC3在胃腺癌中与上皮-间质转化(EMT)间的关系。 方法 采用免疫组织化学方法对2013年10月—2014年10月蚌埠医学院第一附属医院病理科存档的113例胃腺癌标本及相应的癌旁组织标本进行TACC3、E-钙黏附蛋白(E-cadherin)和波形蛋白(Vimentin)的表达分析。 结果 TACC3、E-cadherin、Vimentin在胃腺癌标本和相应癌旁组织中的阳性表达率分别为67.3%、45.1%、50.4%和17.7%、69.9%、27.4%,差异有统计学意义。Kaplan-Meier生存分析表明,TACC3和Vimentin阳性表达的患者生存时间(OST)比阴性表达的患者短,差异有统计学意义(均P < 0.001)。E-cadherin表达阳性的患者生存时间高于阴性表达组(P < 0.001)。多因素分析显示TACC3和Vimentin的阳性表达及E-cadherin阴性表达是GAC的独立预后因素(均P < 0.05);Spearman相关分析显示TACC3与Vimentin的表达呈正相关,E-cadherin与TACC3的表达呈负相关,E-cadherin和Vimentin的表达呈负相关(均P < 0.001)。 结论 TACC3的高表达在胃腺癌中与EMT及不良预后相关。TACC3有望成为胃腺癌靶向治疗的新靶点,同时TACC3早期检测结果有望成为评估胃腺癌患者转移和预后的指标之一。 -
关键词:
- 转录相关酸性卷曲蛋白3 /
- 上皮-间质转化 /
- 胃腺癌 /
- 预后
Abstract:Objective To investigate the expression of transforming acidic coiled-coil protein-3 (TACC3) in gastric adenocarcinoma (GAC) and explore the relationship between the expressions of TACC3 and epithelial-mesenchymal transition (EMT) and the clinicopathological parameters of patients. Methods A total of 113 GAC specimens and corresponding matched normal tissue specimens filed in Departments of Pathology, the First Affiliated Hospital of Bengbu Medical College from October 2013 to October 2014 were analysed for TACC3, E-cadherin and vimentin protein expressions by immunohistochemical staining. Results The positive expression rates of TACC3, E-cadherin and vimentin in GAC specimens and normal gastric tissues were 67.3%, 45.1%, 50.4% and 17.7%, 69.9%, 27.4%, respectively. The difference was statistically significant. Kaplan-Meier survival analysis showed that the survival time of patients with positive expression of TACC3 and vimentin was lower than that of patients with negative expression, and the difference was statistically significant (all P < 0.001). Patients who had positive expression of E-cadherin had a significantly higher OST than those with negative expression (P < 0.001). Multivariate analysis demonstrated that the positive expression of TACC3 and vimentin and the negative expression of E-cadherin were independent prognostic factors for GAC (all P < 0.05). Spearman correlation coefficient analysis showed that the expressions of TACC3 and vimentin were positively related. The relationship between E-cadherin and TACC3 was negatively correlated. The relationship between E-cadherin and vimentin was negatively correlated (all P < 0.001). Conclusion High expression of TACC3 is found to be related to EMT and poor prognosis in GAC. TACC3 is expected to become a new target for GAC targeted therapy, and early detection of TACC3 expression can be used to evaluate the metastasis and prognosis of GAC patients. -
表 1 不同临床特征胃腺癌患者胃腺癌组织中TACC3、E-cadherin、Vimentin表达情况比较(例)
Table 1. Different clinical features of gastric carcinoma patients with gastric adenocarcinoma tissues TACC3, E - cadherin, Vimentin expression in comparison (cases)
项目 TACC3 χ2值 P值 E-cadherin χ2值 P值 Vimentin χ2值 P值 + - + - + - 性别 1.963 0.161 1.713 0.191 0.169 0.681 男性 57 32 43 46 44 45 女性 19 5 8 16 13 11 年龄(岁) 0.459 0.498 2.086 0.149 0.003 0.953 ≤56 20 12 11 21 16 16 >56 56 25 40 41 41 40 分化程度 8.686 0.034 16.978 0.001 12.285 0.006 Ⅰ 2 2 2 2 1 3 Ⅱ 28 20 31 17 16 32 Ⅲ 15 10 11 14 16 9 差分化 31 5 7 29 24 12 TNM分期 8.164 0.004 8.740 0.003 8.882 0.003 0~Ⅱ 22 21 27 16 14 29 Ⅲ~Ⅳ 54 16 24 46 43 27 淋巴结转移 9.975 0.002 4.669 0.031 4.943 0.026 是 56 16 27 45 42 30 否 20 21 24 17 15 26 表 2 单因素生存分析结果
Table 2. Results of univariate survival analysis
项目 例数 术后总生存时间(x±s,月) log-rank χ2值 P值 TACC3 21.959 < 0.001 阴性 37 40.8±3.1 阳性 76 24.0±1.4 Vimentin 27.119 < 0.001 阴性 57 37.3±2.4 阳性 56 21.9±1.4 E-cadherin 27.889 < 0.001 阴性 51 22.5±1.5 阳性 62 37.5±2.4 性别 1.402 0.236 男 89 30.7±1.9 女 24 24.5±2.2 年龄(岁) 0.002 0.965 ≤56 32 28.7±2.3 >56 81 29.7±2.0 分化程度 26.267 < 0.001 Ⅰ 4 50.8±9.7 Ⅱ 48 33.3±2.1 Ⅲ 25 30.5±3.7 差分化 36 20.1±1.3 淋巴结转移 19.227 < 0.001 否 41 38.2±2.9 是 72 24.2±1.4 TNM分期 29.818 < 0.001 0~Ⅱ 43 40.8±3.0 Ⅲ~Ⅳ 70 22.7±1.6 表 3 多因素生存分析结果
Table 3. Results of multivariate survival analysis
项目 B SE Wald χ2 P值 RR值 95% CI TACC3 -0.591 0.257 5.307 0.021 0.554 0.335~0.916 E-cadherin 0.491 0.242 4.120 0.042 1.635 1.017~2.628 Vimentin -0.520 0.236 4.849 0.028 0.594 0.374~0.944 分化程度 0.624 0.307 4.129 0.042 0.536 0.293~0.978 淋巴结转移 -0.523 0.257 4.419 0.021 0.554 0.335~0.916 TNM分期 0.746 0.254 6.621 0.003 2.108 1.281~3.467 表 4 胃腺癌组织中TACC3、E-cadherin和Vimentin间的相关性分析
Table 4. Correlation analysis of TACC3, E-cadherin and Vimentin in gastric adenocarcinoma
项目 TACC3(例) r值 P值 E-cadherin(例) r值 P值 阴性 阳性 阴性 阳性 Vimentin 0.402 < 0.001 -0.488 < 0.001 阴性 29 27 17 39 阳性 8 49 45 12 E-cadherin -0.352 < 0.001 阴性 11 51 阳性 26 25 -
[1] BRAY F, FERLAY J, SOERJOMATARAM I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68(6): 394-424. doi: 10.3322/caac.21492 [2] VENERITO M, LINK A, ROKKAS T, et al. Review: Gastric cancer-clinical aspects[J]. Helicobacter, 2019, 24: e12643. DOI: 10.1111/hel.12643. [3] STRONG V E. Progress in gastric cancer[J]. Updates Surg, 2018, 70(2): 157-159. doi: 10.1007/s13304-018-0543-3 [4] 张英杰, 梁金荣. 腹腔镜胃癌根治术治疗进展期胃癌患者的近期疗效及对腹腔内微转移的影响[J]. 中华全科医学, 2017, 15(11): 1867-1869, 1890. doi: 10.16766/j.cnki.issn.1674-4152.2017.11.013ZHANG Y J, LIANG Y R. Short-term efficacy of laparoscopic radical gastrectomy for advanced gastric cancer and its influence on intra-abdominal micrometastases[J]. Chinese general practice, 2017, 15(11): 1867-1869, 1890. doi: 10.16766/j.cnki.issn.1674-4152.2017.11.013 [5] COSTA R, CARNEIRO B A, TAXTER T, et al. FGFR3-TACC3 fusion in solid tumors: Mini review[J]. Oncotarget, 2016, 7(34): 55924-55938. doi: 10.18632/oncotarget.10482 [6] FRATTINI V, PAGNOTTA S M, TALA, et al. A metabolic function of FGFR3-TACC3 gene fusions in cancer[J]. Nature, 2018, 553(7687): 222-227. doi: 10.1038/nature25171 [7] LIN Z R, WANG M Y, HE S Y, et al. TACC3 transcriptionally upregulates E2F1 to promote cell growth and confer sensitivity to cisplatin in bladder cancer[J]. Cell Death Dis, 2018, 9(2): 72. doi: 10.1038/s41419-017-0112-6 [8] DING Z M, HUANG C J, JIAO X F, et al. The role of TACC3 in mitotic spindle organization[J]. Cytoskeleton(Hoboken), 2017, 74(10): 369-378. [9] CAMPO L, BREUER E K. Inhibition of TACC3 by a small molecule inhibitor in breast cancer[J]. Biochemi Biophys Res Commun, 2018, 498(4): 1085-1092. doi: 10.1016/j.bbrc.2018.03.125 [10] MA W J, GU Y K, PENG J H, et al. Pretreatment TACC3 expression in locally advanced rectal cancer decreases the response to neoadjuvant chemoradiotherapy[J]. Aging, 2018, 10(10): 2755-2771. doi: 10.18632/aging.101585 [11] WANG Y, DING X, HU H, et al. Long non-coding RNA lnc-PCTST predicts prognosis through inhibiting progression of pancreatic cancer by downregulation of TACC-3[J]. Int J Cancer, 2018, 143(12): 3143-3154. doi: 10.1002/ijc.31657 [12] 石斌, 樊平, 许方方. 白细胞介素1β对结直肠癌细胞HCT116迁移能力和上皮-间质转化的影响[J]. 安徽医学, 2019, 40(10): 1079-1083. doi: 10.3969/j.issn.1000-0399.2019.10.001SHI B, FAN P, XU F F. Effects of interleukin-1β on the migration ability and epithelial-mesenchymal transition of colorectal cancer cells HCT116[J]. Anhui Medical Journal, 2019, 40(10): 1079-1083. doi: 10.3969/j.issn.1000-0399.2019.10.001 [13] XIA P, XU X Y. Epithelial-mesenchymal transition and gastric cancer stem cell[J]. Tumour Biol, 2017. DOI: 10.1177/1010428317698373. [14] DONGRE A, WEINBERG R A. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer[J]. Nat Rev Mol Cell Biol, 2019, 20(2): 69-84. [15] LU W, KANG Y. Epithelial-mesenchymal plasticity in cancer progression and metastasis[J]. Dev Cell, 2019, 49(3): 361-374. doi: 10.1016/j.devcel.2019.04.010 [16] ALLEMANI C, MATSUDA T, DI CARLO V, et al. Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): Analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries[J]. Lancet, 2018, 391(10125): 1023-1075. doi: 10.1016/S0140-6736(17)33326-3 [17] 王珣, 张鹏, 刘智明, 等. MiR-22靶向调控CD151促进胃癌血管新生的机制研究[J]. 中华全科医学, 2018, 16(12): 1984-1988. doi: 10.16766/j.cnki.issn.1674-4152.000541WANG X, ZHANG P, LIU Z M, et al. Study on the mechanism of MiR-22 targeting CD151 to promote angiogenesis in gastric cancer[J]. Chinese general practice, 2018, 16(12): 1984-1988. doi: 10.16766/j.cnki.issn.1674-4152.000541 [18] AKBULUT O, LENGERLI D, SAATCI O, et al. A highly potent TACC3 inhibitor as a novel anticancer drug candidate[J]. Mol Cancer Ther, 2020, 19(6): 1243-1254. doi: 10.1158/1535-7163.MCT-19-0957 [19] LASORELLA A, SANSON M, IAVARONE A. FGFR-TACC gene fusions in human glioma[J]. Neuro Oncol, 2017, 19(4): 475-483. [20] JOHNSTON K J, WEN H, HOCKENBERRY J M, et al. Association between patient cognitive and functional status and medicare total annual cost of care: Implications for value-based payment[J]. JAMA Intern Med, 2018, 178(11): 1489-1497. doi: 10.1001/jamainternmed.2018.4143 [21] DHAMI J, HIRSHFIELD K M, GANESAN S, et al. Comprehensive genomic profiling aids in treatment of a metastatic endometrial cancer[J]. Cold Spring Harb Mol Case Stud, 2018, 4(2). DOI: 10.1101/mcs.a002089. [22] MATSUDA K, MIYOSHI H, HIRAOKA K, et al. Elevated expression of transforming acidic coiled-coil containing protein 3 (TACC3) is associated with a poor prognosis in osteosarcoma[J]. Clin Orthop Relat Res, 2018, 476(9): 1848-1855. doi: 10.1097/CORR.0000000000000379 [23] 张益玮, 彭秀达, 肖帅. 上皮-间充质转变的概念变迁及与肿瘤转移研究进展[J]. 中国普通外科杂志, 2020, 29(2): 241-247. https://www.cnki.com.cn/Article/CJFDTOTAL-ZPWZ202002020.htmZHANG Y W, PENG X D, XIAO S. Conceptual changes of epithelial-mesenchymal transition and research progress on tumor metastasis[J]. Chinese Journal of General Surgery, 2020, 29(2): 241-247. https://www.cnki.com.cn/Article/CJFDTOTAL-ZPWZ202002020.htm [24] PAKULA M, PIETRASIK M J, WITUCKA A, et al. The epithelial-mesenchymal transition initiated by malignant ascites underlies the transmesothelial invasion of ovarian cancer cells[J]. Int J Mol Sci, 2019, 20(1): 137. doi: 10.3390/ijms20010137