淋巴样增强因子-1在胰腺导管腺癌中的表达及对预后的影响

摘要/Abstract

摘要：

目的研究Wnt信号通路中淋巴样增强因子-1(LEF-1)在胰腺导管腺癌(PDAC)中的表达及其意义。方法采用荧光定量PCR检测人PDAC细胞株PANC-1和正常胰腺导管上皮细胞株HPDE6中LEF-1 mRNA的相对表达情况;收集2012年6月至2013年12月新疆医科大学附属肿瘤医院肝胆胰外科保存的胰腺癌组织标本45例及其对应的癌旁组织标本45例,应用免疫组织化学法检测癌组织及癌旁组织中LEF-1的表达情况,分析LEF-1的表达与患者临床病理特征和预后的关系。结果荧光定量PCR示PANC-1细胞株中LEF-1 mRNA的相对表达量明显高于HPDE-6细胞株(2.895±0.485vs.1.006±0.126,t=3.056,P<0.001)。免疫组织化学结果显示,LEF-1在癌组织中高表达33例(73.3%),高于癌旁组织的12例(26.7%),差异有统计学意义(χ²=14.815,P<0.001);LEF-1的表达与术前糖类抗原(CA)19-9水平(P<0.001)、局部淋巴结转移(P=0.041)有关。生存分析示,PDAC患者整体中位总生存期(OS)为22.0个月,LEF-1高表达患者(n=33)中位OS为19.0个月,LEF-1低表达患者(n=12)中位OS为31.0个月,差异有统计学意义(χ²=5.554,P=0.018)。单因素Cox回归分析结果显示,与OS相关的因素有年龄(HR=1.962,95%CI为1.043~3.692,P=0.037)、LEF-1(HR=2.253,95%CI为1.097~4.630,P=0.027)和CA19-9(HR=2.667,95%CI为1.258~5.656,P=0.011)。多因素Cox回归分析示,CA19-9(HR=6.431,95%CI为1.078~38.382,P=0.041)、CA125(HR=0.151,95%CI为0.027~0.839,P=0.031)、原发肿瘤大小(HR=8.364,95%CI为1.925~36.335,P=0.005)、LEF-1(HR=2.281,95%CI为1.025~5.075,P=0.043)是影响PDAC患者预后的独立危险因素。结论LEF-1在PDAC组织中表达上调,与术前CA19-9水平、局部淋巴结转移呈正相关,是PDAC患者预后的独立影响因素。

关键词:淋巴样增强子结合因子1,Wnt信号通路,胰腺肿瘤,预后

Abstract:

ObjectiveTo investigate the expression of lymphoid enhancement factor-1 (LEF-1) in Wnt signaling pathway in pancreatic ductal adenocarcinoma (PDAC) and its significance.MethodsThe relative expressions of LEF-1 mRNA in human PDAC cell line PANC-1 and normal pancreatic ductal epithelial cell line HPDE6 were detected by fluorescence quantitative PCR. A total of 45 pancreatic cancer tissue specimens and their corresponding paracancerous tissue specimens were collected from the Department of Hepatobiliary and Pancreatic Surgery, Affiliated Tumor Hospital of Xinjiang Medical University from June 2012 to December 2013. The expressions of LEF-1 in the cancer tissues and paracancerous tissues were detected by immunohistochemistry, and the relationships between LEF-1 expression and clinicopathological characteristics and prognosis of patients were analyzed.ResultsFluorescence quantitative PCR showed that the relative expression level of LEF-1 mRNA in PANC-1 cell line was significantly higher than that in HPDE-6 cell line (2.895±0.485vs.1.006±0.126,t=3.056,P<0.001). Immunohistochemical results showed that LEF-1 was highly expressed in 33 cases (73.3%) of cancer tissues, which was higher than that in 12 cases (26.7%) of adjacent tissues, and there was a statistically significant difference (χ²=14.815,P<0.001). LEF-1 expression was correlated with preoperative carbohydrate antigen (CA) 19-9 level (P<0.001) and local lymph node metastasis (P=0.041). Survival analysis showed that the median overall survival (OS) was 22.0 months in patients with PDAC, 19.0 months in patients with high LEF-1 expression (n=33), 31.0 months in patients with low LEF-1 expression (n=12), and there was a statistically significant difference (χ²=5.554, P=0.018). Univariate Cox regression analysis showed that age (HR=1.962, 95%CI: 1.043-3.692,P=0.037), LEF-1 (HR=2.253, 95%CI: 1.097-4.630,P=0.027), and CA19-9 (HR=2.667, 95%CI: 1.258-5.656, P=0.011) were associated with OS. Multivariate Cox regression analysis showed that CA19-9 (HR=6.431, 95%CI: 1.078-38.382,P=0.041), CA125 (HR=0.151, 95%CI: 0.027-0.839,P=0.031), primary tumor size (HR=8.364, 95%CI: 1.925-36.335,P=0.005), LEF-1 (HR=2.281, 95%CI: 1.025-5.075,P=0.043) were independent risk factors affecting the prognosis of PDAC patients.ConclusionLEF-1 expression is up-regulated in PDAC tissues, which is positively correlated with preoperative CA19-9 level and local lymph node metastasis, and is an independent prognostic factor in patients with PDAC.

Key words:Lymphoid enhancer-binding factor 1,Wnt signaling pathway,Pancreatic neoplasms,Prognosis

李珂珂, 孔盼盼, 易超, 王喜艳, 晏冬. 淋巴样增强因子-1在胰腺导管腺癌中的表达及对预后的影响[J]. 国际肿瘤学杂志, 2021, 48(10): 608-613.

Li Keke, Kong Panpan, Yi Chao, Wang Xiyan, Yan Dong. Expression of lymphoid enhancer factor-1 in pancreatic ductal adenocarcinoma and its effect on prognosis[J]. Journal of International Oncology, 2021, 48(10): 608-613.

图/表5

图1

表1

LEF-1的表达与PDAC患者临床病理特征的关系(例)"

临床病理特征	例数	LEF-1		χ²值	P值	临床病理特征	例数	LEF-1		χ²值	P值
临床病理特征	例数	高表达	低表达	χ²值	P值	临床病理特征	例数	高表达	低表达	χ²值	P值
性别						肿瘤大小(cm)
男性	27	20	7	0.019	0.891	≤2.0	11	8	3
女性	18	13	5			2.1~4.0	22	18	4	―	0.379
年龄(岁)						>4.0	12	7	5
≤60	24	17	7	0.164	0.685	肿瘤浸润情况
>60	21	16	5			无浸润	24	16	8
BMI(kg/m²)						十二指肠黏膜层	2	2	0
<18.5	2	2	0			十二指肠黏膜下层	4	2	2	―	0.440
18.5~23.9	19	14	5	―	>0.999	十二指肠肌层	5	4	1
≥24.0	24	17	7			十二指肠浆膜层	10	9	1
糖尿病						局部淋巴结转移
无	37	29	8	―	0.181	无	18	10	8	―	0.041
有	8	4	4			有	27	23	4
术前总胆红素(μmol/L)						TNM分期
≤17.1	13	11	2	―	0.460	Ⅰa	2	1	1
>17.1	32	22	10			Ⅰb	14	9	5
术前直接胆红素(μmol/L)						Ⅱa	11	7	4	―	0.301
≤6.8	16	13	3	―	0.491	Ⅱb	17	15	2
>6.8	29	20	9			Ⅲ	1	1	0
术前CA19-9(U/ml)						肿瘤分化程度
≤40	12	4	8	―	<0.001	高分化	16	9	7
>40	33	29	4			中分化	14	13	1	―	0.089
术前CA125(U/ml)						低分化	15	11	4
≤35	37	26	11	―	0.419
>35	8	7	1

表1

图2

表2

45例PDAC患者总生存期单因素Cox回归分析"

临床病理特征	HR值	95% CI	P值
性别	1.585	0.849~2.958	0.148
年龄	1.962	1.043~3.692	0.037
BMI	0.819	0.475~1.412	0.472
有无糖尿病	1.989	0.880~4.496	0.099
术前总胆红素	0.580	0.295~1.140	0.114
术前直接胆红素	0.615	0.321~1.176	0.142
CA19-9	2.667	1.258~5.656	0.011
CA125	0.801	0.369~1.739	0.575
原发肿瘤大小	1.242	0.855~1.804	0.254
原发肿瘤浸润情况	0.909	0.764~1.081	0.279
局部淋巴结转移	1.150	0.625~2.114	0.654
肿瘤分期	1.123	0.841~1.501	0.432
肿瘤分化	1.124	0.793~1.593	0.513
LEF-1	2.253	1.097~4.630	0.027

表2

临床病理特征	β值	SE值	Wald值	HR值	95%CI	P值
CA19-9	1.861	0.911	4.170	6.431	1.078~38.382	0.041
CA125	-1.893	0.876	4.665	0.151	0.027~0.839	0.031
原发肿瘤大小	2.124	0.749	8.033	8.364	1.925~36.335	0.005
LEF-1	0.825	0.408	4.086	2.281	1.025~5.075	0.043

表3

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