Analysis of relationship between RAS pathway related genes and cervical cancer metastasis using bioinformatics methods

doi:10.3877/cma.j.issn.1674-0785.2022.02.002

Abstract

Abstract:

Objective

To analyze the relationship between the Ras signaling pathway and cervical cancer metastasis using bioinformatics methods, in order to explore the key molecules of signal pathways closely related to the development of cervical cancer.

Methods

The signaling pathways regulated by miR-3162-5p were analyzed and high-scoring pathways related to the development of cervical cancer were selected. Oncomine was used to retrieve the expression of genes in the pathway in cervical cancer, and the differentially expressed genes were screened out. Protein-protein interaction network (PPI) and module analysis were constructed using STRING and Cytoscape.

Results

A total of 77 differentially expressed genes were screened by bioinformatics methods, including 31 highly expressed genes, 42 lowly expressed genes, and 4 genes with different expression trends. Among them, 24 key genes were identified. Survival analysis showed that protein tyrosine phosphatase non-receptor type 11 (PTPN11), vascular endothelial growth factor A (VEGFA), insulin like growth factor 1 (IGF1), fibroblast growth factor receptor 2 (FGFR2), G protein subunit gamma 7 (GNG7), and KIT ligand (KITLG) may be involved in the occurrence, development, invasion, and recurrence of cervical cancer. The results of immunohistochemistry suggested that PTPN11 was expressed differentially between cervical cancer tissue and cervical non-cancerous epithelium, and the difference was statistically significant (P＜0.05).

Conclusion

The differential genes and key genes identified in this study are helpful to understand the molecular mechanism of cervical cancer occurrence and development, and provide candidate targets for the diagnosis and treatment of this malignancy.

Key words: Cervical squamous cell carcinoma, RAS pathway, Differential genes, Survival analysis, Immunohistochemistry

Qiaoqiao Huang, Junying Chen, Jinbing Huang, Wensheng Xu, Erling Chen. Analysis of relationship between RAS pathway related genes and cervical cancer metastasis using bioinformatics methods[J]. Chinese Journal of Clinicians(Electronic Edition), 2022, 16(02): 112-123.

/ / Recommend

Add to citation manager EndNote|Ris|BibTeX

URL: https://zhlcyszz.cma-cmc.com.cn/EN/10.3877/cma.j.issn.1674-0785.2022.02.002

https://zhlcyszz.cma-cmc.com.cn/EN/Y2022/V16/I02/112

Figures/Tables 10

References 41

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.
2	Wang T, Wu MH, Wu YM, et al. A population-based study of invasive cervical cancer patients in Beijing: 1993-2008 [J]. Chin Med J (Engl), 2015, 128(24): 3298-3304.
3	Shi WJ, Liu H, Wu D, et al. E6/E7 proteins are potential markers for the screening and diagnosis of cervical pre-cancerous lesions and cervical cancer in a Chinese population [J]. Oncol Lett, 2017, 14(5): 6251-6258.
4	Ayala-Calvillo E, Mojica-Vázquez LH, García-Carrancá A, et al. Wnt/β-catenin pathway activation and silencing of the APC gene in HPV-positive human cervical cancer-derived cells [J]. Mol Med Rep, 2018, 17(1): 200-208.
5	Yoshimatsu Y, Nakahara T, Tanaka K, et al. Roles of the PDZ-binding motif of HPV 16 E6 protein in oncogenic transformation of human cervical keratinocytes [J]. Cancer Sci, 2017, 108(7): 1303-1309.
6	陈军莹, 姚德生, 贺婵娟, 等. 宫颈鳞癌MicroRNA差异表达的研究 [J]. 实用医学杂志, 2014, 30(1): 83-87.
7	Chen J, Yao D, Zhao S, et al. MiR-1246 promotes SiHa cervical cancer cell proliferation, invasion, and migration through suppression of its target gene thrombospondin 2 [J]. Arch Gynecol Obstet, 2014, 290(4): 725-732.
8	陈军莹, 姚德生, 李悦等. 早期子宫颈鳞癌伴淋巴结转移患者癌组织中差异微小RNA的表达 [J]. 中华妇产科杂志,2014, 49(3): 226-228.
9	Stiasny A, Kuhn C, Mayr D, et al. Immunohistochemical evaluation of E6/E7 HPV oncoproteins staining in cervical cancer [J]. Anticancer Res, 2016, 36(6): 3195-3198.
10	Golden RJ, Chen B, Li T, et al. An Argonaute phosphorylation cycle promotes microRNA-mediated silencing [J]. Nature, 2017, 542(7640): 197-202.
11	Gorbea C, Mosbruger T, Cazalla D. A viral Sm-class RNA base-pairs with mRNAs and recruits microRNAs to inhibit apoptosis [J]. Nature, 2017, 550(7675): 275-279.
12	Han CW, Jeong MS, Jang SB. Molecular interaction between K-Ras and H-REV107 in the Ras signaling pathway [J]. Biochem Biophys Res Commun, 2017, 491(2): 257-264.
13	Dorard C, Vucak G, Baccarini M. Deciphering the RAS/ERK pathway in vivo [J]. Biochem Soc Trans, 2017, 45(1): 27-36.
14	Hobbs GA, Der CJ, Rossman KL. RAS isoforms and mutations in cancer at a glance [J]. J Cell Sci, 2016, 129(7): 1287-1292.
15	Basu SK, Lee S, Salotti J, et al. Oncogenic RAS-induced perinuclear signaling complexes requiring KSR1 regulate signal transmission to downstream targets [J]. Cancer Res, 2018, 78(4): 891-908.
16	Delire B, Stärkel P. The Ras/MAPK pathway and hepatocarcinoma: pathogenesis and therapeutic implications [J]. Eur J Clin Invest, 2015, 45(6): 609-623.
17	Ritt DA, Abreu-Blanco MT, Bindu L, et al. Inhibition of Ras/Raf/MEK/ERK pathway signaling by a stress-induced phospho-regulatory circuit [J]. Mol Cell, 2016, 64(5): 875-887.
18	Hu YC, Wang AM, Lu JK, et al. Long noncoding RNA HOXD-AS1 regulates proliferation of cervical cancer cells by activating Ras/ERK signaling pathway [J]. Eur Rev Med Pharmacol Sci, 2017, 21(22): 5049-5055.
19	Wu Y, Gu TT, Zheng PS. CIP2A cooperates with H-Ras to promote epithelial-mesenchymal transition in cervical-cancer progression [J]. Cancer Lett, 2015, 356(2 Pt B): 646-655.
20	Zou Y, Liu FY, Wu J, et al. Mutational analysis of the RAS/RAF/MEK/ERK signaling pathway in 260 Han Chinese patients with cervical carcinoma [J]. Oncol Lett, 2017, 14(2): 2427-2431.
21	Wang Z, Liu Z, Fang X, et al. MiR-142-5p suppresses tumorigenesis by targeting PIK3CA in non-small cell lung cancer [J]. Cell Physiol Biochem, 2017, 43(6): 2505-2515.
22	Xu JM, Wang Y, Wang YL, et al. PIK3CA mutations contribute to acquired cetuximab resistance in patients with metastatic colorectal cancer [J]. Clin Cancer Res, 2017, 23(16): 4602-4616.
23	Keegan NM, Gleeson JP, Hennessy BT, et al. PI3K inhibition to overcome endocrine resistance in breast cancer [J]. Expert Opin Investig Drugs, 2018, 27(1): 1-15.
24	Chung TKH, Cheung TH, Yim SF, et al. Liquid biopsy of PIK3CA mutations in cervical cancer in Hong Kong Chinese women [J]. Gynecol Oncol, 2017, 146(2): 334-339.
25	Zhao H, Martin E, Matalkah F, et al. Conditional knockout of SHP2 in ErbB2 transgenic mice or inhibition in HER2-amplified breast cancer cell lines blocks oncogene expression and tumorigenesis [J]. Oncogene, 2018, 38(13):2275-2290.
26	Hill KS, Roberts ER, Wang X, et al. PTPN11 plays oncogenic roles and is a therapeutic target for BRAF wild-type melanomas [J]. Mol Cancer Res, 2018, 17(2):583-593.
27	Bejar R. What biologic factors predict for transformation to AML? [J] Best Pract Res Clin Haematol, 2018, 31(4): 341-345.
28	Mainardi S, Mulero-Sánchez A, Prahallad A, et al. SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo [J]. Nat Med, 2018, 24(7): 961-967.
29	Coulombe G, Rivard N. New and unexpected biological functions for the src-homology 2 domain-containing phosphatase SHP-2 in the gastrointestinal tract [J]. Cell Mol Gastroenterol Hepatol, 2016, 2(1): 11-21.
30	Xiang D, Cheng Z, Liu H, et al. Shp2 promotes liver cancer stem cell expansion by augmenting β-catenin signaling and predicts chemotherapeutic response of patients [J]. Hepatology, 2017, 65(5): 1566-1580.
31	Zhang J, Zhang F, Niu R. Functions of Shp2 in cancer [J]. J Cell Mol Med, 2015, 19(9): 2075-2083.
32	Fedele C, Ran H, Diskin B, et al. SHP2 inhibition prevents adaptive resistance to MEK inhibitors in multiple cancer models [J]. Cancer Discov, 2018, 8(10): 1237-1249.
33	Xie J, Si X, Gu S, et al. Allosteric inhibitors of SHP2 with therapeutic potential for cancer treatment [J]. J Med Chem, 2017, 60(24): 10205-10219.
34	Yan D, Zhu D, Zhao X, Su J. SHP-2 restricts apoptosis induced by chemotherapeutic agents via Parkin-dependent autophagy in cervical cancer [J]. Cancer Cell Int, 2018, 15(18): 8.
35	Liu JJ, Li Y, Chen WS, et al. Shp2 deletion in hepatocytes suppresses hepatocarcinogenesis driven by oncogenic β-Catenin, PIK3CA and MET [J]. J Hepatol, 2018, 69(1): 79-88.
36	Aiello NM, Brabletz T, Kang Y, et al. Upholding a role for EMT in pancreatic cancer metastasis [J]. Nature, 2017, 547(7661): E7-E8.
37	Li XW, Tuergan M, Abulizi G. Expression of MAPK1 in cervical cancer and effect of MAPK1 gene silencing on epithelial-mesenchymal transition, invasion and metastasis [J]. Asian Pac J Trop Med, 2015, 8(11): 937-943.
38	Li W, Liang J, Zhang Z, et al. MicroRNA-329-3p targets MAPK1 to suppress cell proliferation, migration and invasion in cervical cancer [J]. Oncol Rep, 2017, 37(5): 2743-2750.
39	Chen B, Zhang C, Dong P, et al. Molecular regulation of cervical cancer growth and invasion by VEGFa [J]. Tumour Biol, 2014, 35(11): 11587-11593.
40	Sablania P, Batra S, Saxena A. Insulin-like growth factor I receptor (IGF-IR) ligands and BMI in squamous intra-epithelial lesion (SIL) of cervix [J]. J Clin Diagn Res, 2016, 10(2): BC11-5.
41	Roszik J, Ring KL, Wani KM, et al. Gene expression analysis identifies novel targets for cervical cancer therapy [J]. Front Immunol, 2018, 9: 2102.

顺序	通路	P值	基因数
1	粘蛋白型O-聚糖生物合成（hsa00512）	2.106410x10^-8	6
2	脂肪酸链延伸（hsa00062）	0.001115	4
3	吗啡成瘾（hsa05032）	0.001223	12
4	GABA能突触（hsa04727）	0.002484	13
5	尼古丁成瘾（hsa05033）	0.008949	10
6	细胞因子-细胞因子受体相互作用（hsa04060）	0.010831	28
7	TGF-β信号通路（hsa04350）	0.022676	13
8	Ras信号通路（hsa04014）	0.025450	34
9	苯丙胺成瘾（hsa05031）	0.031152	12
10	脂肪酸代谢（hsa01212）	0.040433	6

顺序	通路	P值	基因数
1	粘蛋白型O-聚糖生物合成（hsa00512）	2.106410x10^-8	6
2	脂肪酸链延伸（hsa00062）	0.001115	4
3	吗啡成瘾（hsa05032）	0.001223	12
4	GABA能突触（hsa04727）	0.002484	13
5	尼古丁成瘾（hsa05033）	0.008949	10
6	细胞因子-细胞因子受体相互作用（hsa04060）	0.010831	28
7	TGF-β信号通路（hsa04350）	0.022676	13
8	Ras信号通路（hsa04014）	0.025450	34
9	苯丙胺成瘾（hsa05031）	0.031152	12
10	脂肪酸代谢（hsa01212）	0.040433	6

表达	基因
高表达差异基因（31个）	PDGFA，VEGFA，EFNA，IGF1R，MET，PTPN11，GNB1，GNB4，GNB5，GNG5，CALML4，MRAS，RRAS2，NF1，PAK2，PIK3CA，AKT1，AKT3，IKBKG，IKBKA，MAP2K1，MAPK1，ETS2，BRAP，RAP1B，MAPK9，TBK1，CDC42，PLCE，ABL2，RAB5C
低表达差异基因（42个）	TGFA，FGF1，FGF2，FGF7，FGF22，BDNF，NTF3，IGF1，IGF2，PDGFC，PDGFD，KITLG，ANGPT2，FGFR1，FGFR2，NTRK2，PDGFRB，KIT，FLT1，TEK，EPHA2，GAB1，GAB2，SHC2，SHC3，GNG7，GNG11，GRIN1，GRIN2B，CALML3，CALML5，RASAL1，RASAL2，PIK3R1，PLA2G3，PLA2G1B，cPLA2-beta，KSR1，RALB，MAPK10，PRKCB，RAB5A
既存在高表达趋势又存在低表达趋势差异基因（4个）	RASGRF1，RAC2，PLD1，PRKCA

表达	基因
高表达差异基因（31个）	PDGFA，VEGFA，EFNA，IGF1R，MET，PTPN11，GNB1，GNB4，GNB5，GNG5，CALML4，MRAS，RRAS2，NF1，PAK2，PIK3CA，AKT1，AKT3，IKBKG，IKBKA，MAP2K1，MAPK1，ETS2，BRAP，RAP1B，MAPK9，TBK1，CDC42，PLCE，ABL2，RAB5C
低表达差异基因（42个）	TGFA，FGF1，FGF2，FGF7，FGF22，BDNF，NTF3，IGF1，IGF2，PDGFC，PDGFD，KITLG，ANGPT2，FGFR1，FGFR2，NTRK2，PDGFRB，KIT，FLT1，TEK，EPHA2，GAB1，GAB2，SHC2，SHC3，GNG7，GNG11，GRIN1，GRIN2B，CALML3，CALML5，RASAL1，RASAL2，PIK3R1，PLA2G3，PLA2G1B，cPLA2-beta，KSR1，RALB，MAPK10，PRKCB，RAB5A
既存在高表达趋势又存在低表达趋势差异基因（4个）	RASGRF1，RAC2，PLD1，PRKCA

条目	描述	基因数目	率值
GO：0007169	跨膜受体蛋白酪氨酸激酶信号通路	15	8.42E-17
GO：0007167	酶联受体蛋白信号通路	16	5.02E-16
GO：0030334	细胞迁移调控	11	1.08E-10
GO：0007166	细胞表面受体连接的信号转导	20	2.93E-10
GO：0040012	运动调节	11	3.91E-10
GO：0051270	细胞运动调节	11	4.12E-10
GO：0008284	正向调控细胞增殖	13	8.80E-10
GO：0030335	细胞迁移的正向调控	9	1.76E-09
GO：0051272	对细胞运动的正向调节	9	3.89E-09
GO：0040017	运动的正向调节	9	3.89E-09
GO：0007243	蛋白激酶级联反应	12	8.53E-09
GO：0016310	磷酸化	14	9.92E-08
GO：0007242	细胞内信号级联	16	1.11E-07
GO：0006793	磷代谢过程s	14	1.13E-06
GO：0042127	细胞增殖调节	13	1.58E-06

Please choose a citation manager

Content to export