Abstract
Background
Colon cancer is one of most malignant cancers around worldwide. Nearly 20% patients were diagnosed at colon cancer with metastasis. However, the lack of understanding regarding its pathogenesis brings difficulties to study it.
Methods
In this study, we acquired high‐sequence data from GEO dataset, and performed integrated bioinformatic analysis including differently expressed genes, gene ontology and Kyoto Encyclopedia of Genes and Genomes pathways analysis, protein–protein analysis, survival analysis to analyze the development of colon cancer.
Results
By comparing the colon cancer tissues with normal colon tissues, 109 genes were dysregulated; among them, 83 genes were downregulated and 26 genes were upregulated. Two clusters were founded based on the STRING database and MCODE plugin of cytoscape software. Then, six genes with prognostic value were filtered out in UALCAN website.
Conclusion
We found that SPP1, VIP, COL11A1, CA2, ADAM12, INHBA could provide great significant prognostic value for colon cancer.
Keywords: bioinformatic analysis, colon cancer, GEO, TCGA
1. INTRODUCTION
Colon cancer, one of the most malignant cancers around worldwide, has caused more than 50,000 deaths per year (Haggar & Boushey, 2009). Due to the characters of colon cancer, such as incidence hidden, progression rapidly, prone to resistant to chemotherapy (He et al., 2017; Marin et al., 2012), it has brought seriously social and medical burden which arose public concern.
Although large‐scale studies have been carried on to investigate the early diagnosis biomarkers and the mechanism of colon cancer, it is easy for us to be lost in the dense fog when treating colon cancer. Giving to the contribution of the second‐generation gene sequencing (Kamps et al., 2017), it is much helpful for us to uncover the causes and pathogenesis of colon cancer as well as identifying novel biomarkers with great prognostic value.
In this study, we perform integrated analysis including differently expressed genes, gene ontology (GO) analysis, KEGG pathway analysis, survival analysis both to identify a panel of key candidate genes involved in colon cancer, and we found that SPP1, VIP, COL11A1, CA2, ADAM12, and INHBA could provide great significant prognostic value for colon cancer.
2. MATERIALS AND METHODS
2.1. Ethical compliance
The clinical information and sequence data were acquired according to the requirements of GEO and TCGA databanks. Thus, no ethics committee approval or consent procedure was needed.
2.2. Data source
High‐sequence data of GSE62932 (GPL570, Affymetrix Human Genome U133 Plus 2.0 Array) were collected from GEO dataset, which includes 68 colon tissues until 03 June 2018. As GEO is a publicly available dataset, no ethics approval is required. The samples were divided into two groups based on the sample type, a total of 64 colon cancer tissues and 4 normal colon tissues were utilized for the following analysis.
2.3. Differently expressed genes in colon cancer
Prior to analyzing the DEGs (differently expressed genes) in colon cancer, the sequence data were normalized using RMA (Robust Multichip Average). Then, we performed DEGs analysis using limma package with the cutoff of p‐value <0.05 and |logFC| ≥ 2 (Robinson, McCarthy, & Smyth, 2010). The heatmap was shown by pheatmap R package based on the expression value of DEGs. To better understand how the DEGs involved in the biological process and the signal transduction process, the clusterprofiler R package was carried on the GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis (Yu, Wang, Han, & He, 2012), a p‐value <0.05 was considered significant.
2.4. Protein–protein network analysis
As genes were interacting with each other, to deep excavate the central genes, STRING database was applied to construct the interaction network of genes (Szklarczyk et al., 2017). Cytoscape software was performed to visualize the relationship between genes (Shannon et al., 2003). For the sake of further research, following the protein–protein network analysis, the MCODE plugin was performed to re‐analyze the clusters among the network according to the k‐core = 2.
2.5. Survival analysis to screen the candidate genes
Survival analysis was carried on the UALCAN website (Chandrashekar et al., 2017), which is a portal for survival analysis according to the TCGA dataset. The colon cancer samples were divided into two groups according to gene expression: high expression (with Transcripts per million [TPM] values higher median) and low/median expression (with TPM values lower median). Then, we used the Kaplan–Meier method to analyze the candidate genes of significantly prognostic value with a p‐value <0.05.
2.6. Validation in TCGA and The Human Protein Atlas
For validation, the candidate genes were assessed both from RNA expression level and protein level by TCGA data portal and The Human Protein Atlas database, respectively. The GEPIA website was applied to exhibit the relative RNA expression level between colon cancer and normal colon tissues while The Human Protein Atlas database was performed to map the protein in the tissues (Tang et al., 2017; Uhlén et al., 2015).
3. RESULTS
3.1. Differently expressed genes involved in colon cancer
In this part, samples were first grouped based on the pathology of colon tissues as colon cancer tissues and normal colon tissues, respectively. Differently expressed genes analysis was performed in succession with the p‐value <0.05 and |logFC| ≥ 2. One hundred and nine genes were dysregulated, among them, 83 genes were downregulated and 26 genes were upregulated. To further evaluate the genes’ function, we performed GO analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The upregulated genes are mainly enriched in C‐X‐C chemokine receptor(CXCR) binding, cytokine activity, chemokine activity, chemokine receptor binding, G‐protein coupled receptor binding, IL‐17 signaling pathway, rheumatoid arthritis, cytokine‐cytokine receptor interaction, chemokine signaling pathway, Toll‐like receptor signaling pathway. The downregulated genes were mostly enriched in oxidoreductase activity, acting on the CH–OH group of donors, nicotinamide adenine dinucleotide (NAD) or nicotinamide adenine dinucleotide phosphate (NADP) as acceptor, carbonate dehydratase activity, chloride channel activity, inorganic anion transmembrane transporter activity, oxidoreductase activity, acting on CH–OH group of donors, retinol metabolism, pentose and glucuronate interconversions, bile secretion, drug metabolism ‐ cytochrome P450, metabolism of xenobiotics by cytochrome P450 (Figure 1).
3.2. Protein–protein network analysis
To deep excavate the key genes involved in the development of colon cancer, we take STRING website to estimate the interaction relationship between genes. One thousand three hundred and twenty‐six pairs involved with 229 proteins were constructed in Cytoscape software (Figure 2). We then utilized MCODE plugin to find densely connected regions based on topology and two dense clusters were discovered. Cluster 1 involved 23 genes and 113 connections (SULF1, NPY1R, CXCL8, FGFR2, CXCL5, LEF1, CCL28, HBB, CXCL3, CXCL10, MMP3, CHL1, INHBA, GCG, LPAR1, CHGA, CD36, SPINK5, SFRP4, ANPEP, GZMB, CXCL11, P2RY14). Cluster 2 involved 23 genes and 94 connections(HOPX, SPP1, NOX4, DPT, COL10A1, MMP11, ADAM12, LAMA1, COL11A1, SFRP1, MMP1, CA2, SST, CA1, THBS2, CFD, MMP9, VIP, ABCG2, CHI3L1, MMP7, COL4A5, CNTN3). The density of our protein‐protein network was confirmed with the high degree of nodes, suggesting common competitions for colon cancer.
3.3. Survival analysis of key genes
To seek the candidate genes which may influence the survival outcome, we perform the survival analysis on the key genes. A total of six candidate genes were screened and were found to have impact on overall survival days, which are SPP1, VIP, COL11A1, CA2, ADAM12, INHBA, respectively (Figure 3). Patients whose tissues have a higher expression of SPP1, VIP, COL11A1, ADAM12, INHBA had significantly shorter overall survival compared to those with lower expression, while patients with higher expression of CA2 have a better prognosis.
3.4. Validation in TCGA and the Human Protein Atlas
The RNA expression levels of SPP1, VIP, COL11A1, CA2, ADAM12, and INHBA were validated in TCGA dataset. Due to the lack of COL11A1 and INHBA information in The Human Protein Atlas dataset, the protein expression level was not evaluated (Figure 4). The results also supported that SPP1, COL11A1, ADAM12, and INHBA expressions were significantly higher in colon cancer tissues compared to that of the normal tissues in accordance with our previous study.
4. DISCUSSION
In this study, we performed several bioinformatics analyses to excavate key genes involved in development of colon cancer. At first, 109 dysregulated genes were found through the comparison between the normal colon tissues and the colon cancer tissues. Protein–protein network analysis was followed to study the interactions between differently expressed genes and also cluster was studied in succession. Then, we performed survival analysis on those key genes to search the prognostic value genes. Interestingly, we found a total of six genes which are SPP1, VIP, COL11A, CA2, ADAM12, INHBA. We go a step further to validate them both in RNA expression level and protein expression level, also, the results are in accordance with our pervious study.
SPP1, a secreted phosphoprotein which contains RGD domain, was firstly separated from bone matrix as an extracellular matrix protein by Herring (Heinegård, Hultenby, Oldberg, Reinholt, & Wendel, 1989; Oldberg, Franzén, & Heinegård, 1986). It is vital in bone reconstruction, anti‐inflammation, arteriosclerosis, and immunomodulation. A variety of cell types including osteoclast, macrophage, epithelial cells, T cells, endothelial cells could secrete SPP1 (Saitoh, Kuratsu, Takeshima, Yamamoto, & Ushio, 1995). Besides, many studies hold the opinion that SPP1 participates in the development and metastasis of malignant tumor. In gastric cancer (Imano et al., 2009), esophageal cancer (Lin et al., 2015), glioma (Ellert‐Miklaszewska et al., 2016), breast cancer (Rodrigues, Teixeira, Schmitt, Paulsson, & Lindmark‐Mänsson, 2007), lung cancer (Chambers et al., 1996). It was upregulated and might have served as a biomarker. Also, it could promote ovarian cancer proliferation, migration and invasion in vitro by activating Integrin β1/FAK/AKT signaling pathway (Zeng, Zhou, Wu, & Xiong, 2018). Also, the recent study showed that SPP1 could mediate macrophage polarization and lung cancer evasion, which could be used as a promising drug target (Zhang, Du, Chen, & Xiang, 2017).
COL11A1 encodes one of the two alpha chains of type XI collagen, a minor fibrillar collagen. It has been widely studied in many cancers. It is overexpressed in both adenocarcinoma and squamous cell lung carcinoma, comparing with the corresponding non‐neoplastic lung tissues (Wang et al., 2002), in metastatic oral cavity/pharynx squamous cell carcinoma (Schmalbach et al., 2004). Also, it was involved in lymph node metastasis in breast cancer (Feng et al., 2007) which could be used as a potential biomarker to distinguish malignant from premalignant lesions in stomach and pancreas cancer (Kleinert et al., 2015; Zhao et al., 2009). It is localized in the Golgi apparatus of normal human colon goblet cells (Bowen et al., 2008). COL11A1 may be associated with the APC/beta‐catenin pathway in FAP and sporadic colon cancer (Fischer et al., 2001). In lung cancer, it has a positive correlation with pathology stage, poor prognosis, and lymph node metastasis (Chong et al., 2006), it promotes ovarian cancer progression and chemoresistance to cisplatin and paclitaxel via activating NF‐KB, and it promotes the expression of TWIST1, MCL1(Wu, Huang, Chang, & Chou, 2017). It has also been reported that COL11A1 was upregulated in gastric cancer and non‐small cell lung cancer which could boost the malignant behavior in vitro (Li, Li, Lin, Zhuo, & Si, 2017; Shen et al., 2016). COL11A1 could be utilized as a promising biomarker in predicting malignant relapse of breast intraductal papilloma (Freire et al., 2015).
Carbonic anhydrase (CA) II is a member of carbonic anhydrases, which are a ubiquitous group of zinc‐bound metalloenzymes and catalyze the reversible hydration of carbon dioxide. Carbonic anhydrase II (hCAII) has important function in physiology and pathology process. CA II highly expresses in different normal organs, but its expression is inhibited in cancer cells (Li, Xie et al., 2012; Sheng, Dong, Zhou, Li, & Dong, 2013). CA II is also associated with osteopetrosis and renal tubular acidosis (Borthwick et al., 2003). CA II takes part in keeping the adequate balance between carbon dioxide and bicarbonate and controls the pH level in cells. As we know that the carbon dioxide and bicarbonate balance is the basic life activities, and can influence various cell behaviors, the low expression of CA II may play important roles in tumor progress and development.
ADAM12 (ADisintegrin and metalloproteinase domain‐containing protein 12) encodes a member of a family of proteins, which play important role in a variety of biological processes involving cell‐cell and cell‐matrix interactions (Roy, Wewer, Zurakowski, Pories, & Moses, 2004). ADAM12 have different isoform, that shorter isoforms are secreted, while longer isoforms are membrane‐bound form. AMDAM12 takes part in the regulation in physic and pathological progress, including muscle development, neurogenesis, and fertilization. ADAM12 is upregulated in various cancer, including breast, prostate, ovarian, skin, stomach, lung and brain cancers (Li, Duhachek‐Muggy et al., 2012; Shao et al., 2014). ADAM12 contributes to tumor progression and metastasis by promoting tumor cell proliferation, migration, invasion, and apoptosis resistance.
INHBA is a member of the TGF‐beta (transforming growth factor‐beta) superfamily. INHBA gene is overexpressed in different kinds of cancer, such as colorectal cancer, pancreatic cancer, and lung cancer, and promotes cell proliferation, invasion, metastasis and chemoresistance in cancer cells (Okano et al., 2013; Oshima et al., 2014). INHBA also takes part in the development of eye, tooth and testis. INHBA can form different kind of protein complex, which can activate and inhibit follicle stimulating hormone secretion from the pituitary gland, respectively.
In conclusion, in this study, we performed integrated analysis to discover the differently expressed genes involved in the development of colon cancer, also showed a panel of genes with prognostic values to better evaluate the outcome of colon cancer patients. Here, we found that SPP1, VIP, COL11A1, CA2, ADAM12, and INHBA exhibited some significant prognostic values. More in‐depth studies are needed to determine the biological functions and mechanisms through which these genes impact cancer malignant cell behavior. Also, the expression pattern of these genes may be a promising target for therapy in colon cancer.
CONFLICT OF INTEREST
None declared.
Supporting information
ACKNOWLEDGMENTS
None.
Yang H, Wu J, Zhang J, et al. Integrated bioinformatics analysis of key genes involved in progress of colon cancer. Mol Genet Genomic Med. 2019;7:e588 10.1002/mgg3.588
Contributor Information
Hua Liu, Email: yyyyliuhua@163.com.
Zhenyi Wang, Email: yyyywangzhenyi@163.com.
REFERENCES
- Borthwick, K. J. , Kandemir, N. , Topaloglu, R. , Kornak, U. , Bakkaloglu, A. , Yordam, N. , … Karet, F. E. (2003). A phenocopy of CAII deficiency: A novel genetic explanation for inherited infantile osteopetrosis with distal renal tubular acidosis. Journal of Medical Genetics, 40(2), 115–121. 10.1136/jmg.40.2.115 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bowen, K. B. , Reimers, A. P. , Luman, S. , Kronz, J. D. , Fyffe, W. E. , & Oxford, J. T. (2008). Immunohistochemical localization of collagen type XI alpha1 and alpha2 chains in human colon tissue. Journal of Histochemistry and Cytochemistry, 56(3), 275–283. 10.1369/jhc.7a7310.2007 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chambers, A. F. , Wilson, S. M. , Kerkvliet, N. , O'Malley, F. P. , Harris, J. F. , & Casson, A. G. (1996). Osteopontin expression in lung cancer. Lung Cancer, 15(3), 311–323. 10.1016/0169-5002(95)00595-1 [DOI] [PubMed] [Google Scholar]
- Chandrashekar, D. S. , Bashel, B. , Balasubramanya, S. A. H. , Creighton, C. J. , Rodriguez, I. P. , Chakravarthi, B. V. S. K. , & Varambally, S. (2017). UALCAN: A portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia, 19(8), 649–658. 10.1016/j.neo.2017.05.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chong, I. W. , Chang, M. Y. , Chang, H. C. , Yu, Y. P. , Sheu, C. C. , Tsai, J. R. , … Lin, S. R. (2006). Great potential of a panel of multiple hMTH1, SPD, ITGA11 and COL11A1 markers for diagnosis of patients with non‐small cell lung cancer. Oncology Reports, 16(5), 981–988. [PubMed] [Google Scholar]
- Ellert‐Miklaszewska, A. , Wisniewski, P. , Kijewska, M. , Gajdanowicz, P. , Pszczolkowska, D. , Przanowski, P. , … Kaminska, B. (2016). Tumour‐processed osteopontin and lactadherin drive the protumorigenic reprogramming of microglia and glioma progression. Oncogene, 35(50), 6366–6377. 10.1038/onc.2016.55 [DOI] [PubMed] [Google Scholar]
- Feng, Y. , Sun, B. , Li, X. , Zhang, L. , Niu, Y. , Xiao, C. , … Hao, X. (2007). Differentially expressed genes between primary cancer and paired lymph node metastases predict clinical outcome of node‐positive breast cancer patients. Breast Cancer Research and Treatment, 103(3), 319–329. 10.1007/s10549-006-9385-7 [DOI] [PubMed] [Google Scholar]
- Fischer, H. , Salahshor, S. , Stenling, R. , Björk, J. , Lindmark, G. , Iselius, L. , … Lindblom, A. (2001). COL11A1 in FAP polyps and in sporadic colorectal tumors. BMC Cancer, 1, 17 10.1186/1471-2407-1-17 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Freire, J. , García‐Berbel, L. , García‐Berbel, P. , Pereda, S. , Azueta, A. , García‐Arranz, P. , … Gómez‐Román, J. (2015). Collagen type XI alpha 1 expression in intraductal papillomas predicts malignant recurrence. BioMed Research International, 2015, 812027 10.1155/2015/812027 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Haggar, F. A. , & Boushey, R. P. (2009). Colorectal cancer epidemiology: Incidence, mortality, survival, and risk factors. Clinics in Colon and Rectal Surgery, 22(4), 191–197. 10.1055/s-0029-1242458 [DOI] [PMC free article] [PubMed] [Google Scholar]
- He, J. , Pei, L. , Jiang, H. , Yang, W. , Chen, J. , & Liang, H. (2017). Chemoresistance of colorectal cancer to 5‐fluorouracil is associated with silencing of the BNIP3 gene through aberrant methylation. Journal of Cancer, 8(7), 1187–1196. 10.7150/jca.18171 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Heinegård, D. , Hultenby, K. , Oldberg, A. , Reinholt, F. , & Wendel, M. (1989). Macromolecules in bone matrix. Connective Tissue Research, 21(1–4), 3–11; discussion 12–4. 10.3109/03008208909049990 [DOI] [PubMed] [Google Scholar]
- Imano, M. , Satou, T. , Itoh, T. , Sakai, K. , Ishimaru, E. , Yasuda, A. , … Ohyanagi, H. (2009). Immunohistochemical expression of osteopontin in gastric cancer. Journal of Gastrointestinal Surgery, 13(9), 1577–1582. 10.1007/s11605-009-0955-y [DOI] [PubMed] [Google Scholar]
- Kamps, R. , Brandão, R. D. , van den Bosch, B. J. , Paulussen, A. D. C. , Xanthoulea, S. , Blok, M. J. , & Romano, A. (2017). Next‐generation sequencing in oncology: Genetic diagnosis, risk prediction and cancer classification. International Journal of Molecular Sciences, 18(2), 308 10.3390/ijms18020308 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kleinert, R. , Prenzel, K. , Stoecklein, N. , Alakus, H. , Bollschweiler, E. , Hölscher, A. , & Warnecke‐Eberz, U. (2015). Gene expression of Col11A1 is a marker not only for pancreas carcinoma but also for adenocarcinoma of the papilla of vater, discriminating between carcinoma and chronic pancreatitis. Anticancer Research, 35(11), 6153–6158. [PubMed] [Google Scholar]
- Li, H. , Duhachek‐Muggy, S. , Qi, Y. , Hong, Y. , Behbod, F. , & Zolkiewska, A. (2012). An essential role of metalloprotease‐disintegrin ADAM12 in triple‐negative breast cancer. Breast Cancer Research and Treatment, 135(3), 759–769. 10.1007/s10549-012-2220-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Li, A. , Li, J. , Lin, J. , Zhuo, W. , & Si, J. (2017). COL11A1 is overexpressed in gastric cancer tissues and regulates proliferation, migration and invasion of HGC‐27 gastric cancer cells in vitro. Oncology Reports, 37(1), 333–340. 10.3892/or.2016.5276 [DOI] [PubMed] [Google Scholar]
- Li, X. J. , Xie, H. L. , Lei, S. J. , Cao, H. Q. , Meng, T. Y. , & Hu, Y. L. (2012). Reduction of CAII expression in gastric cancer: Correlation with invasion and metastasis. Chinese Journal of Cancer Research, 24(3), 196–200. 10.1007/s11670-012-0196-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lin, J. , Myers, A. L. , Wang, Z. , Nancarrow, D. J. , Ferrer‐Torres, D. , Handlogten, A. , … Lin, L. (2015). Osteopontin (OPN/SPP1) isoforms collectively enhance tumor cell invasion and dissemination in esophageal adenocarcinoma. Oncotarget, 6(26), 22239–22257. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Marin, J. J. , Sanchez de Medina, F. , Castaño, B. , Bujanda, L. , Romero, M. R. , Martinez‐Augustin, O. , …, Briz, O. (2012). Chemoprevention, chemotherapy, and chemoresistance in colorectal cancer. Drug Metabolism Reviews, 44(2), 148–172. 10.3109/03602532.2011.638303 [DOI] [PubMed] [Google Scholar]
- Okano, M. , Yamamoto, H. , Ohkuma, H. , Kano, Y. , Kim, H. , Nishikawa, S. , … Ishii, H. (2013). Significance of INHBA expression in human colorectal cancer. Oncology Reports, 30(6), 2903–2908. 10.3892/or.2013.2761 [DOI] [PubMed] [Google Scholar]
- Oldberg, A. , Franzén, A. , & Heinegård, D. (1986). Cloning and sequence analysis of rat bone sialoprotein (osteopontin) cDNA reveals an Arg‐Gly‐Asp cell‐binding sequence. Proceedings of the National Academy of Sciences of the United States of America, 83(23), 8819–8823. 10.1073/pnas.83.23.8819 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Oshima, T. , Yoshihara, K. , Aoyama, T. , Hasegawa, S. , Sato, T. , Yamamoto, N. , … Masuda, M. (2014). Relation of INHBA gene expression to outcomes in gastric cancer after curative surgery. Anticancer Research, 34(5), 2303–2309. [PubMed] [Google Scholar]
- Robinson, M. D. , McCarthy, D. J. , & Smyth, G. K. (2010). edgeR: A Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics, 26(1), 139–140. 10.1093/bioinformatics/btp616 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rodrigues, L. R. , Teixeira, J. A. , Schmitt, F. L. , Paulsson, M. , & Lindmark‐Mänsson, H. (2007). The role of osteopontin in tumor progression and metastasis in breast cancer. Cancer Epidemiology, Biomarkers & Prevention, 16(6), 1087–1097. [DOI] [PubMed] [Google Scholar]
- Roy, R. , Wewer, U. M. , Zurakowski, D. , Pories, S. E. , & Moses, M. A. (2004). ADAM 12 cleaves extracellular matrix proteins and correlates with cancer status and stage. Journal of Biological Chemistry, 279(49), 51323–51330. [DOI] [PubMed] [Google Scholar]
- Saitoh, Y. , Kuratsu, J. , Takeshima, H. , Yamamoto, S. , & Ushio, Y. (1995). Expression of osteopontin in human glioma. Laboratory Investigation, 72(1), 55–63. [PubMed] [Google Scholar]
- Schmalbach, C. E. , Chepeha, D. B. , Giordano, T. J. , Rubin, M. A. , Teknos, T. N. , Bradford, C. R. , … Hanash, S. (2004). Molecular profiling and the identification of genes associated with metastatic oral cavity/pharynx squamous cell carcinoma. Archives of Otolaryngology ‐ Head and Neck Surgery, 130(3), 295–302. [DOI] [PubMed] [Google Scholar]
- Shannon, P. , Markiel, A. , Ozier, O. , Baliga, N. S. , Wang, J. T. , Ramage, D. , … Ideker, T. (2003). Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Research, 13(11), 2498–2504. 10.1101/gr.1239303 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shao, S. , Li, Z. , Gao, W. , Yu, G. , Liu, D. , & Pan, F. (2014). ADAM‐12 as a diagnostic marker for the proliferation, migration and invasion in patients with small cell lung cancer. PLoS ONE, 9(1), e85936 10.1371/journal.pone.0085936 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shen, L. , Yang, M. , Lin, Q. , Zhang, Z. , Zhu, B. , & Miao, C. (2016). COL11A1 is overexpressed in recurrent non‐small cell lung cancer and promotes cell proliferation, migration, invasion and drug resistance. Oncology Reports, 36(2), 877–885. 10.3892/or.2016.4869 [DOI] [PubMed] [Google Scholar]
- Sheng, W. , Dong, M. , Zhou, J. , Li, X. , & Dong, Q. (2013). Down regulation of CAII is associated with tumor differentiation and poor prognosis in patients with pancreatic cancer. Journal of Surgical Oncology, 107(5), 536–543. 10.1002/jso.23282 [DOI] [PubMed] [Google Scholar]
- Szklarczyk, D. , Morris, J. H. , Cook, H. , Kuhn, M. , Wyder, S. , Simonovic, M. , … von Mering, C. (2017). The STRING database in 2017: Quality‐controlled protein–protein association networks, made broadly accessible. Nucleic Acids Research, 45(D1): D362–D368. 10.1093/nar/gkw937 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tang, Z. , Li, C. , Kang, B. , Gao, G. , Li, C. , & Zhang, Z. (2017). GEPIA: A web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Research, 45(W1), W98–W102. 10.1093/nar/gkx247 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Uhlén, M. , Fagerberg, L. , Hallström, B. M. , Lindskog, C. , Oksvold, P. , Mardinoglu, A. , … Pontén, F. (2015). Proteomics. Tissue‐based map of the human proteome. Science, 347(6220), 1260419 10.1126/science.1260419 [DOI] [PubMed] [Google Scholar]
- Wang, K. K. , Liu, N. , Radulovich, N. , Wigle, D. A. , Johnston, M. R. , Shepherd, F. A. , … Tsao, M. S. (2002). Novel candidate tumor marker genes for lung adenocarcinoma. Oncogene, 21(49), 7598–7604. 10.1038/sj.onc.1205953 [DOI] [PubMed] [Google Scholar]
- Wu, Y. H. , Huang, Y. F. , Chang, T. H. , & Chou, C. Y. (2017). Activation of TWIST1 by COL11A1 promotes chemoresistance and inhibits apoptosis in ovarian cancer cells by modulating NF‐κB‐mediated IKKβ expression. International Journal of Cancer, 141(11), 2305–2317. 10.1002/ijc.30932 [DOI] [PubMed] [Google Scholar]
- Yu, G. , Wang, L. G. , Han, Y. , & He, Q. Y. (2012). clusterProfiler: An R package for comparing biological themes among gene clusters. OMICS: A Journal of Integrative Biology, 16(5), 284–287. 10.1089/omi.2011.0118 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zeng, B. , Zhou, M. , Wu, H. , & Xiong, Z. (2018). SPP1 promotes ovarian cancer progression via Integrin β1/FAK/AKT signaling pathway. OncoTargets and Therapy, 12(11), 1333–1343. 10.2147/ott.s154215 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhang, Y. , Du, W. , Chen, Z. , & Xiang, C. (2017). Upregulation of PD‐L1 by SPP1 mediates macrophage polarization and facilitates immune escape in lung adenocarcinoma. Experimental Cell Research, 359(2), 449–457. 10.1016/j.yexcr.2017.08.028 [DOI] [PubMed] [Google Scholar]
- Zhao, Y. , Zhou, T. , Li, A. , Yao, H. , He, F. , Wang, L. , & Si, J. (2009). A potential role of collagens expression in distinguishing between premalignant and malignant lesions in stomach. The Anatomical Record, 292(5), 692–700. 10.1002/ar.20874 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.