Clinical significance of expression of FOXM1 and GRP78 proteins in advanced gastric cancer

doi:10.3877/cma.j.issn.1674-0785.2019.08.002

Abstract

Abstract:

Objective

To investigate the expression of forkhead box M1 (FOXM1) and glucose-regulated protein 78 (GRP78) in advanced gastric cancer and to analyze their clinical value.

Methods

Immunohistochemical technique was used to detect the expression of FOXM1 and GRP78 proteins in cancerous and paracancerous tissues from 168 patients with advanced gastric cancer. χ² test was used to analyze the correlation between the pathological features of advanced gastric cancer and the expression of FOXM1 and GRP78. Prognostic risk factors for advanced gastric cancer were analyzed by Cox single- and multiple-factor analyses.

Results

The positive rates of FOXM1 and GRP78 expression in advanced gastric cancer were 53.57% (90/168) and 67.26% (113/168), respectively. No or weak expression of FOXM1 and GRP78 was found in paracancerous tissues. The expression of FOXM1 was positively related to expression of GRP78 in gastric cancer tissues (r=0.41, P<0.001). The expression of FOXM1 protein was correlated with cancer embolus (P<0.001), lymph node metastasis (P<0.001), T stage (P<0.001), TNM stage (P<0.001), and tumor differentiation (P<0.001). The expression of GRP78 protein was correlated with cancer embolus (P=0.003), lymph node metastasis (P=0.002), and tumor differentiation (P<0.001). The overall survival of patients with positive expression of both FOXM1 and GRP78 was shorter than those with negative expression of both proteins (χ²=35.1189, P<0.001). FOXM1 and T stage were independent prognostic factors for advanced gastric cancer.

Conclusion

FOXM1 and GRP78 may be involved in the development and progression of gastric cancer, and they might become new targets for clinical therapy for advanced gastric cancer.

Key words: Advanced gastric cancer, Forkhead box M1, Glucose-regulated protein 78

Jun Gong, Feng Sun, Conghui Jin, Jianjuan Ge, Jiaye Song, Lei Yang. Clinical significance of expression of FOXM1 and GRP78 proteins in advanced gastric cancer[J]. Chinese Journal of Clinicians(Electronic Edition), 2019, 13(08): 566-571.

/ / Recommend

Add to citation manager EndNote|Ris|BibTeX

URL: https://zhlcyszz.cma-cmc.com.cn/EN/10.3877/cma.j.issn.1674-0785.2019.08.002

https://zhlcyszz.cma-cmc.com.cn/EN/Y2019/V13/I08/566

Figures/Tables 5

References 22

1	王长明，许超，卫子然, 等. 进展期胃癌新辅助化疗前后IL-6 IL-10的变化及其临床意义[J/CD]. 中华临床医师杂志(电子版), 2012, 6(15): 4290-4294.
2	Parkin DM, Bray F, Ferlay J, et al. Parkin DM, Bray F, Ferlay J and Pisani PEstimating the world cancer burden: Globocan 2000[J]. Int J Cancer, 2001, 94(2): 153-156.
3	Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012[J]. CA Cancer J Clin, 2015, 65(2): 87-108.
4	Gong A, Huang S. FoxM1 and Wnt/β-catenin signaling in glioma stem cells[J]. Cancer Res, 2012, 72(22): 5658-5662.
5	Raychaudhuri P, Park HJ. FoxM1: a master regulator of tumor metastasis[J]. Cancer Res, 2011, 71(13): 4329-4333.
6	Wierstra I. FOXM1 (Forkhead box M1) in tumorigenesis: overexpression in human cancer, implication in tumorigenesis, oncogenic functions, tumor-suppressive properties, and target of anticancer therapy[J]. Adv Cancer Res, 2013, 119: 191-419.
7	Sano T, Coit DG, Kim HH, et al. Proposal of a new stage grouping of gastric cancer for TNM classification: International Gastric Cancer Association staging project[J]. Gastric Cancer, 2017, 20(2): 1-9.
8	Yang L, Yang S, Liu J, et al. Expression of GRP78 predicts taxane-based therapeutic resistance and recurrence of human gastric cancer[J]. Exp Mol Pathol, 2014, 96(2): 235-241.
9	Balli D, Zhang Y, Snyder J, et al. Endothelial Cell-specific Deletion of Transcription Factor FOXM1 Increases Urethane-induced Lung Carcinogenesis[J]. Cancer Res, 2011, 71(1): 40-50.
10	Wierstra I, Alves J. FOXM1, a typical proliferation-associated transcription factor[J]. Biol Chem, 2007, 388(12): 1257-1274.
11	Zhang Y, Liu R, Ni M, et al . Cell surface relocalization of the endoplasmic reticulum chaperone and unfolded protein response regulator GRP78/BiP[J]. J Biol Chem 2010, 285(20): 15065-15075.
12	Li Z, Zhang L, Zhao Y, et al. Cell-surface GRP78 facilitates colorectal cancer cell migration and invasion[J]. Int J Biochem Cell Biol, 2013, 45(5): 987-994.
13	Zhang XX, Li HD, Zhao S, et al. The cell surface GRP78 facilitates the invasion of hepatocellular carcinoma cells[J]. Biomed Res Int, 2013, 2013: 917296.
14	Karadedou CT, Gomes AR, Chen J, et al. FOXO3a represses VEGF expression through FOXM1-dependent and -independent mechanisms in breast cancer[J]. Oncogene, 2012, 31(14): 1845-1858.
15	Wang CY, Hua L, Sun J, et al. MiR-211 inhibits cell proliferation and invasion of gastric cancer by down-regulating SOX4[J]. Int J Clin Exp Pathol, 2015, 8(11): 14013-14020.
16	Bella L, Zona S, de Moraes GN, et al. FOXM1: A key oncofoetal transcription factor in health and disease[J]. Semin Cancer Biol, 2014, 29: 32-39.
17	Huang C, Du J, Xie K. FOXM1 and its oncogenic signaling in pancreatic cancer pathogenesis[J]. Biochim Biophys Acta, 2014, 1845(2): 104-116.
18	Huang C, Xie D, Cui J, et al. FOXM1c promotes pancreatic cancer epithelial-to-mesenchymal transition and metastasis via upregulation of expression of the urokinase plasminogen activator system[J]. Clin Cancer Res, 2014, 20(6): 1477-1488.
19	Yang C, Chen H, Tan G, et al. FOXM1 promotes the epithelial to mesenchymal transition by stimulating the transcription of Slug in human breast cancer[J]. Cancer Lett, 2013, 340(1): 104-112.
20	Li D, Wei P, Peng Z, et al. The Critical Role of Dysregulated FOXM1-PLAUR Signaling in Human Colon Cancer Progression and Metastasis[J]. Clin Cancer Res, 2013, 19(1): 62-72.
21	Meng FD, Wei JC, Qu K, et al. FoxM1 overexpression promotes epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma[J]. World J Gastroenterol, 2015, 21(1): 196-213.
22	Koo CY, Muir KW, Lam WF. FOXM1: From cancer initiation to progression and treatment[J]. Biochim Biophys Acta, 2012, 1819(1): 28-37.

临床参数		例数	FOXM1			GRP78
临床参数		例数	阳性	χ²值	P值	阳性	χ²值	P值
年龄（岁）		?	?	0.172	0.678	?	0.914	0.339
?	<50	28	16	?	?	21	?	?
?	≥50	140	74	?	?	92	?	?
性别		?	?	0.286	0.593	?	0.015	0.901
?	男	115	60	?	?	77	?	?
?	女	53	30	?	?	36	?	?
脉管癌栓		?	?	15.520	<0.001	?	8.831	0.003
?	有	46	36	?	?	39	?	?
?	无	122	54	?	?	74	?	?
神经侵犯		?	?	0.054	0.816	?	0.350	0.554
?	有	77	42	?	?	50	?	?
?	无	91	48	?	?	63	?	?
TNM分期		?	?	24.463	<0.001	?	3.949	0.139
?	Ⅰ期	20	9	?	?	13	?	?
?	Ⅱ期	69	23	?	?	41	?	?
?	Ⅲ期	79	58	?	?	59	?	?
T分期		?	?	7.675	0.022	?	1.165	0.559
?	T₂	40	21	?	?	29	?	?
?	T₃	79	35	?	?	50	?	?
?	T₄	49	34	?	?	34	?	?
分化程度		?	?	17.063	<0.001	?	117.596	<0.001
?	高	9	3	?	?	1	?	?
?	中	44	13	?	?	4	?	?
?	低	115	74	?	?	108	?	?
淋巴结转移		?	?	27.882	<0.001	?	15.034	0.002
?	N₀	60	20	?	?	36	?	?
?	N₁	23	8	?	?	11	?	?
?	N₂	45	36	?	?	40	?	?
?	N₃	40	26	?	?	26	?	?

临床参数		例数	FOXM1			GRP78
临床参数		例数	阳性	χ²值	P值	阳性	χ²值	P值
年龄（岁）		?	?	0.172	0.678	?	0.914	0.339
?	<50	28	16	?	?	21	?	?
?	≥50	140	74	?	?	92	?	?
性别		?	?	0.286	0.593	?	0.015	0.901
?	男	115	60	?	?	77	?	?
?	女	53	30	?	?	36	?	?
脉管癌栓		?	?	15.520	<0.001	?	8.831	0.003
?	有	46	36	?	?	39	?	?
?	无	122	54	?	?	74	?	?
神经侵犯		?	?	0.054	0.816	?	0.350	0.554
?	有	77	42	?	?	50	?	?
?	无	91	48	?	?	63	?	?
TNM分期		?	?	24.463	<0.001	?	3.949	0.139
?	Ⅰ期	20	9	?	?	13	?	?
?	Ⅱ期	69	23	?	?	41	?	?
?	Ⅲ期	79	58	?	?	59	?	?
T分期		?	?	7.675	0.022	?	1.165	0.559
?	T₂	40	21	?	?	29	?	?
?	T₃	79	35	?	?	50	?	?
?	T₄	49	34	?	?	34	?	?
分化程度		?	?	17.063	<0.001	?	117.596	<0.001
?	高	9	3	?	?	1	?	?
?	中	44	13	?	?	4	?	?
?	低	115	74	?	?	108	?	?
淋巴结转移		?	?	27.882	<0.001	?	15.034	0.002
?	N₀	60	20	?	?	36	?	?
?	N₁	23	8	?	?	11	?	?
?	N₂	45	36	?	?	40	?	?
?	N₃	40	26	?	?	26	?	?

临床资料	单因素分析			多因素分析
临床资料	P>\|z\|	HR值	95%CI	P>\|z\|	HR值	95%CI
性别（女 vs男）	0.8	1.058	0.682~1.641	-	-	-
发病年龄（<50岁 vs ≥50岁）	0.078	1.624	0.948~2.784	-	-	-
分化程度（G期，中高分化 vs低分化）	0.019	0.601	0.393~0.919	0.562	1.28	0.556~2.947
浸润深度（T期，T₂ vs T_3-4）	0.005	0.491	0.299~0.804	0.013	0.351	0.154~0.804
区域淋巴结转移（N期，N₀ vs N_1-3）	0.005	0.508	0.316~0.816	1.000	1.000	0.483~2.068
TNM分期（Ⅰ期 vs Ⅱ＋Ⅲ期）	<0.001	0.475	0.305~0.738	0.285	0.672	0.324~1.393
脉管癌栓（无 vs有）	0.011	0.529	0.324~0.863	0.639	0.878	0.511~1.509
神经侵犯（否 vs是）	0.465	2.014	1.269~3.195	-	-	-
GRP78蛋白表达（低或无表达 vs高表达）	0.009	0.566	0.37~0.865	0.053	0.447	0.225~1.008
FOXM1蛋白表达（低或无表达 vs高表达）	<0.001	0.267	0.173~0.414	<0.001	0.266	0.164~0.429

临床资料	单因素分析			多因素分析
临床资料	P>\|z\|	HR值	95%CI	P>\|z\|	HR值	95%CI
性别（女 vs男）	0.8	1.058	0.682~1.641	-	-	-
发病年龄（<50岁 vs ≥50岁）	0.078	1.624	0.948~2.784	-	-	-
分化程度（G期，中高分化 vs低分化）	0.019	0.601	0.393~0.919	0.562	1.28	0.556~2.947
浸润深度（T期，T₂ vs T_3-4）	0.005	0.491	0.299~0.804	0.013	0.351	0.154~0.804
区域淋巴结转移（N期，N₀ vs N_1-3）	0.005	0.508	0.316~0.816	1.000	1.000	0.483~2.068
TNM分期（Ⅰ期 vs Ⅱ＋Ⅲ期）	<0.001	0.475	0.305~0.738	0.285	0.672	0.324~1.393
脉管癌栓（无 vs有）	0.011	0.529	0.324~0.863	0.639	0.878	0.511~1.509
神经侵犯（否 vs是）	0.465	2.014	1.269~3.195	-	-	-
GRP78蛋白表达（低或无表达 vs高表达）	0.009	0.566	0.37~0.865	0.053	0.447	0.225~1.008
FOXM1蛋白表达（低或无表达 vs高表达）	<0.001	0.267	0.173~0.414	<0.001	0.266	0.164~0.429

[1]	Lining Shang, Chengzhou Du, Gang Guo, Dehe Chen, Jie Wang, Peng Chen, Hongtao Li. Progress on the study of programmed cell death receptor 1 inhibitors for advanced gastric cancer [J]. Chinese Archives of General Surgery(Electronic Edition), 2022, 16(05): 376-381.
[2]	Yuhao Zhai, Zhi Zheng, Wei Deng, Zhigang Bai, Jie Yin, Jun Zhang. Advances in the controversies of neoadjuvant chemotherapy for advanced gastric cancer [J]. Chinese Archives of General Surgery(Electronic Edition), 2021, 15(05): 386-390.
[3]	Xiaole Su, Bingjuan Yan, Xi Qiao, Yanhong Wang, Lihua Wang. Atorvastatin decreased the contrast-induced renal tubular epithelial cell apoptosis through regulation of the PERK/eIF2α/CHOP signaling pathway [J]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2019, 08(03): 102-108.
[4]	Zhanxue Zhang, Zhong Li, Haiqiang Zhang, Shaofan Qiu, Haijun Wang, Lina Ru, Zhanwen Wang, Tao Li. Clinical comparison of hand assisted laparoscopic gastrectomy with laparotomy and laparoscopy assisted radical gastrectomy for distal gastric cancer [J]. Chinese Journal of Clinicians(Electronic Edition), 2018, 12(04): 212-217.
[5]	Yuanyuan Xiao, Yueqin Mao, Qianqian Wang, Meilin Wei, Junfeng Han, jun Yin, Jinwei Huang, Li Wei. Effects of stress-associated endoplasmic reticulum protein 1 on endoplasmic stress induced by the tunicamycin in HepG2 cells [J]. Chinese Journal of Diagnostics(Electronic Edition), 2014, 02(01): 32-37.

Please choose a citation manager

Content to export