Identification of COL7A1 as a prognostic biomarker in lung squamous cell carcinoma

doi:10.21203/rs.3.rs-1767132/v1

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Identification of COL7A1 as a prognostic biomarker in lung squamous cell carcinoma

https://doi.org/10.21203/rs.3.rs-1767132/v1

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The Collagen Type VII Alpha 1 Chain (COL7A1) is associated with a variety of cancers, however, COL7A1 gene expression in human lung squamous cell carcinoma (LUSC) and its prognostic value have not been well studied. In this study, we used bioinformatics database to analyze the relationship between COL7A1 expression and survival in LUSC patients such as Oncomine, GEPIA, UALCAN, and STRING. And we used Kaplan–Meier plotter to analyze the prognosis of high or low expression of COL7A1 in different patients. We found that COL7A1 was significantly overexpressed in patients with LUSC. Additionally, in the survival analysis, COL7A1 expression was significantly associated with worse overall survival (OS), first progression (FP), Post-progression survival (PPS) in LUSC patients. Moreover, COL7A1 is closely associated with known biomarkers and key factors of LUSC. We used functional annotation enrichment analysis to show that genes co-expressed with COL7A1 were enriched in biological process (BP), cellular component (CC), molecular function (MF) and KEGG pathways. Furthermore, Laminin 332 and its association with COL7A1 may lead to the activation of the PI3K signaling pathway, ultimately leading to squamous cell carcinoma (SCC). This has also been mentioned in other people's research. Therefore, our work was designed to demonstrate the potential of COL7A1 as a prognostic biomarker in LUSC.

bioinformatics analysis

biomarker

COL7A1

lung squamous cell carcinoma

prognosis

Nearly 1.8 million people are diagnosed with lung cancer every year(Ferlay et al. 2015; Torre et al. 2015). Primary lung cancer is one of the common malignant tumors that seriously threaten human health and life. Its morbidity and mortality have increased significantly worldwide, and it has become the leading cause of death from malignant tumors in humans(Chen et al. 2019). The number of deaths per year is higher than that of breast cancer, colorectal cancer, prostate cancer and pancreatic cancer(Lambert and Dransfield 2016). Lung squamous cell carcinoma (LUSC) is a subtype of non-small cell carcinoma, based on age or smoking level, and accounts for approximately 40% of all lung cancers(Kulasingam and Diamandis 2008; Hirsch et al. 2017), and it is a very aggressive malignant tumor with a high rate of metastasis and morbidity. Lung squamous cell carcinoma has unique characteristics including rapid disease progression, more recurrence and strong metastatic ability. As a result, the overall 5-year survival rate of patients with this disease is still very low(Liao et al. 2012; Wang et al. 2020). Clinically, the prognosis and treatment strategy are mainly specified according to the pathological stage of the patient. However, studies often show that there are significant differences in prognosis even in patients with the same postoperative pathological stage. Therefore, it is relatively low to predict the prognosis of patients only according to pathological stage(Guo et al. 2008). It has been reported that during tumor progression, biomarkers are abnormally increased and can be detected in blood, urine and tissues, thus, more specific biomarkers are needed to be identified in order to improve the early detection, diagnosis and prognosis of LUSC.

COL7A1 encodes type VII collagen and is an important molecule in extracellular matrix. Type VII collagen encoded by COL7A1 gene is used as the anchoring fiber of basement membrane, which is different from the collagen forming fiber encoded by type I collagen fiber and the basement membrane collagen encoded by type IV collagen fiber(Burgeson et al. 1990; Ortiz-Urda et al. 2005). It is mainly distributed in stratified squamous epithelium of the dermal epidermal junction of skin, oral mucosa and cervix(Gelse et al. 2003). The immunolocalization study confirmed that type VII collagen is a component of anchored fibers, which extends from the lower part of basement membrane to papillary dermis, and is a completely different attachment structure in morphology(Sakai et al. 1986; Mienaltowski and Birk 2014). COL7A1 gene mutation leads to dystrophic epidermolysis bullosa (RDEB), an incurable and potentially fatal skin disease characterized by chronic skin fragility and blistering(Christiano et al. 1994). When COL7A1 loses its original function due to mutation, squamous cell carcinoma of the skin will increase and show invasion and diffusion potential(Martins et al. 2009). In esophageal squamous cell carcinoma (ESC), recent studies by Baba et al. have showed that the expression of COL7A1 was closely related to poor prognosis(Baba et al. 2006). The expression of COL7A1 in esophageal squamous cell carcinoma and gastric cancer is related to the level of tumor metastasis and prognosis(Kita et al. 2009; Oh et al. 2021). The clinical significance and prognosis of COL7A1 expression in lung squamous cell carcinoma have not been clarified.

The purpose of this study was to demonstrate the clinical significance and prognostic impact of COL7A1 gene overexpression in patients with newly discovered lung squamous cell carcinoma. In our work, we used various such as Oncomine, GEPIA, UALCAN, DAVID and STRING databases to analyze the expression of COL7A1 in LUSC, moreover, we analyzed the impact of LUSC on prognosis and researched the potential mechanism of COL7A1, so as to evaluate the possibility of COL7A1 as a biomarker of lung squamous cell carcinoma.

Oncomine Analysis

Using Oncomine database (https://www.oncomine.org) different data sets and a large number of clinical samples were provided to analyze the expression patterns of COL7A1 mRNA in various types of tumors(Rhodes et al. 2004; Hou et al. 2017). We used Oncomine for meta-analysis of COL7A1 in LUSC, based on a cut-off of p-value ≤ 0.05 and fold change ≥ 2.

UALCAN Analysis

UALCAN (http://ualcan.path.uab.edu/index.html) is a database based on TCGA. We obtained The Cancer Genome Atlas (TCGA) database data(Tomczak et al. 2015; Blum et al. 2018) through UALCAN to analyze the expression of COL7A1 gene in patients with lung squamous cell carcinoma with different clinicopathological characteristics, as well as the mRNA expression level of COL7A1 in patients with lung squamous cell carcinoma with stage, age, smoking habit, lymph node metastasis, molecular subtype and TP53 gene mutation(Chandrashekar et al. 2017; Chandrashekar et al. 2022).

Immunohistochemistry and Antibody

To determine whether the selected target gene can be used as a new biomarker, we used immunohistochemistry to stain the lung tissue sections of patients with lung cancer. The staining method we used was streptavidin-biotin complex (SABC) method. We stained the clinicopathological sections with rabbit anti-collagen VII antibody IgG (Bioss, bs-1558R), SABC Kit (ZSGB-BIO, sp-9001) and DAB chromogenic Kit (ZSGB-BIO, zli-9018). And staining was photographed using a digital imaging microscope, and software was used for data collection (image J)(Jensen 2013). We selected three clinical samples of adjacent tissues and six clinical samples of lung squamous cell carcinoma for difference comparison, and drew the chart according to Welch's t test (GraphPad Prism). We also selected three cases of poorly differentiated, three cases of moderately differentiated and three cases of poorly differentiated clinical samples for statistical analysis by Welch's t test and drew the chart (GraphPad Prism).

STRING Analysis

String database (https://string-db.org/) is a biological database based on known and predicted protein-protein interaction networks and functional interaction analysis between proteins(Szklarczyk et al. 2019; Szklarczyk et al. 2021). Our analysis of protein-protein interactions may help the mechanism of disease development.

Co-expressed Genes

The data were from TCGA database (https://portal.gdc.cancer.gov)(Tomczak et al. 2015; Blum et al. 2018) and analyzed by GEPIA (http://gepia.cancer-pku.cn/)(Tang et al. 2017) to determine the co-expression of COL7A1 gene in patients with lung squamous cell carcinoma.

GO annotation enrichment and KEGG pathway enrichment analysis

GO (gene ontology) annotation collects information from gene ontology and NCBI databases to annotate and classify genes according to biological pathway, molecular function and cell composition(Ashburner et al. 2000; 2021). Through the statistical analysis of GO terms enrichment of differentially expressed genes. KEGG (Kyoto Encyclopedia of genes and genomes) is a comprehensive biological information database, which can predict and analyze pathways and mechanism(Kanehisa and Goto 2000). The analysis of go and KEGG was carried out in DAVID database (https://david.ncifcrf.gov/)(Huang Da et al. 2009; Sherman et al. 2022).

Survival Analysis

Kaplan-Meier plotter (https://kmplot.com/analysis) is a system for evaluating the relationship between gene expression level and survival in a variety of cancers(Győrffy et al. 2013). Kaplan-Meier plotter was used to analyze the effect of high expression and low expression of COL7A1 on prognosis in patients with lung squamous cell carcinoma, and the prognosis of breast cancer was evaluated by the expression of COL7A1 in the form of survival curve. COL7A1 Affymetrix ID: 204136_ at. The critical value of patients with high and low expression of at col7a1de was determined by the median.

COL7A1 expression in lung squamous cell carcinoma

The exploration of tumor biomarkers has always been a prominent research focus. In order to illustrate its role in diagnosis, we queried COL7A1 expression in tumor tissues and normal tissues in the database. The results showed that COL7A1 was upregulated in a variety of tumors as a component of anchored fibers (Fig. 1). In Oncomine database, we found that the expression of COL7A1 in lung cancer was significantly higher than that in normal tissues, including colorectal cancer and head and neck cancer (Fig. 1a). In Bhattacharjee Lung Statistical analysis, the change of COL7A1 mRNA level in LUSC tissue was 4.547 times higher than that in normal tissue (p-value = 5.84E-11, t-test = 8.946) (Fig. 1b), which was plotted by GraphPad Prism 9 according to the data. In the TCGA database in UALCAN, the expression of COL7A1 in patients with lung squamous cell carcinoma was significantly higher than that in normal tissues (p-value = 1.62E-12) (Fig. 1c). Moreover, we determined the expression of COL7A1 in LUSC by immunohistochemistry (Fig. 2a-d), and quantified the expression of COL7A1 by analysis tools (image J). We found that the expression of COL7A1 in lung squamous cell carcinoma was higher than that in adjacent tissues (Fig. 2e). And COL7A1 was not associated with stages of lung squamous cell carcinoma (Fig. 2f).

Expression changes of COL7A1 in different clinical indexes of LUSC

We have verified the up-regulation of COL7A1 expression in lung squamous cell carcinoma through different databases and IHC experiments. Therefore, we further studied the expression pattern of COL7A1 in patients with LUSC through UALCAN database. This database explores the expression of

COL7A1 in various clinicopathological features including stage, age, smoking habit, lymph node metastasis, molecular subtype and TP53 gene mutation. It is worth noting that the high expression of COL7A1 in patients with LUSC shows an upward trend with age, suggesting that age may affect the expression level of COL7A1 (Fig. 3a). In the comparison of cancer stages, the expression of COL7A1 in the normal group was significantly different from different stages, but there was no significant difference between different stages, indicating that there was no close relationship between the stages of COL7A1 LUSC (Fig. 3b). Further, in the comparison of cancer lymph node metastasis with the

normal group, there was no significant difference between the patient groups, suggesting that there was little relationship between the development of tumor and lymph node metastasis. And they also showed that there was no significant difference between the patient groups in the comparison of TP53 mutations, subtypes and smoking habits of patients (Fig. 3c-f).

Association of COL7A1 expression with prognosis in LUSC patients

Kaplan–Meier plotter was used to analyze the relationship between COL7A1 expression and first progression survival (FP), overall survival (OS) and post-progression survival (PPS) in patients with LUSC. As shown in Fig. 4a, the high expression of COL7A1 indicates that first progression (FP) in all patients with lung squamous cell carcinoma is disappointing (HR = 1.4, p = 0.00059). Figure 4b showed that the overall survival (OS) and of patients with high COL7A1 expression were significantly lower than those with low COL7A1 expression (HR = 1.33, P = 8.1E-6), but not statistically significant with post-progress survival (PPS) (HR = 1.24, P = 0.098) (Fig. 4c). Prognostic analysis showed that COL7A1 could be used as an important index to evaluate the prognosis of LUSC. Finally, we used

GEPIA to analyze the staging of COL7A1 in LUSC, and the results showed that COL7A1 had little relationship with tumor stage (Fig. 4d).

Gene co-expression analysis and protein-protein interaction

Based on the above results of COL7A1 expression and prognosis analysis, we chose to further bioinformatics analysis of COL7A1. The first 14 genes co expressed with COL7A1 gene in LUSC were screened from Oncomine database (Fig. 5a). COL7A1 co-expresses with GPC1 (r = 0.817), SERPINB5 (r = 0.752), BNC1 (r = 0.724), PKP1 (r = 0.724), SOX15 (r = 0.724), PVRL1 (r = 0.724), FAT2 (r = 0.732), ANXA8L2 (r = 0.724), S1PR5 (r = 0.724), DST (r = 0.724), TRIM29 (r = 0.724), GJB5 (r = 0.724), IRF6 (r = 0.724), KRT17 (r = 0.724), It could be seen that GPC1 is a related gene.

Further GEPIA analysis shows the correlation between COL7A1 and GPC1 (r = 0.46, p-value = 2E-26), the expression of GPC1 was verified in GEPIA databases (Fig. 5b). We found that GPC1 was significantly up-regulated in lung squamous cell carcinoma (Fig. 5c). Survival analysis of Kaplan-Meier plotter database confirmed that upregulation of GPC1 was closely related to the prognosis of OS in patients with lung squamous cell carcinoma (Fig. 5d). STRING mapped the interaction network between COL7A1 and other proteins to infer the possible role of COL7A1 in LUSC. As showed in Fig. 5e, COL7A1 is closely related and co-expression with MIA3, BMP1, ITGB3, ITGB1, ITGAV, LAMC2, LAMB3, P4HA2, ITGA2, TLL1. At the same time, whether through databases or experiments, it is confirmed that these proteins are closely related to each other.

GO and KEGG enrichment

Based on the results of protein-protein interaction and gene co-expression analysis, we further carried out bioinformatics analysis. By analyzing the gene ontology (GO) and Database Kyoto Encyclopedia of Genes and Genomes (KEGG) for Annotation, Visualization and Integrated Discovery (DAVID), the functions of COL7A1 and the genes significantly related to the changes of COL7A1 were predicted. Go enrichment analysis predicted the function of target host genes from biological process (BP) (Fig. 6a), cell composition (CC) (Fig. 6b) and molecular function (MF) (Fig. 6c). In biological process (BP), we found that GO:0048208 (COPII vesicle coating), GO:0006888 (ER to Golgi vesicle-mediated transport), GO:0030198 (extracellular matrix organization) were significantly regulated by the COL7A1 alterations in LUSC. In cell composition (CC), GO:0012507 (ER to Golgi transport vesicle membrane), GO:0000139 (Golgi membrane) and GO:0030127 (COPII vesicle coat) were obviously controlled by COL7A1 and related genes alteration. Moreover, in molecular function (MF), we could see that GO:0031418 (L-ascorbic acid binding) and GO:0004656 (procollagen-proline 4-dioxygenase activity) were obviously regulated by the COL7A1 and related genes alterations in LUSC. KEGG analysis can determine the pathways related to the functional changes of COL7A1 and related genes (Fig. 6d). Through KEGG analysis, 10 pathways related to the functional changes of COL7A1 in lung squamous cell carcinoma were found. Among them, hsa04512: ECM-receptor interaction, hsa05222: Small cell lung cancer, has04510: Focal adhesion might be involved in the occurrence and pathogenesis of lung squamous cell carcinoma.

COL7A1 encodes type VII collagen and is an important molecule in extracellular matrix and this gene disorders have been reported in many cancers(Kita et al. 2009; O'toole 2014; Geng et al. 2020; Oh et al. 2021). However, further bioinformatics analysis of COL7A1 in lung squamous cell carcinoma has not been carried out. Our study is the first to explore the mRNA expression and prognostic (FP, OS and PPS) value of COL7A1 in lung squamous cell carcinoma. The identification of novel biomarkers for LUSC is crucial to its diagnosis, therapy and prognosis. Therefore, it is of great clinical significance to explore the therapeutic molecules related to prognosis by studying the mechanism of lung squamous cell carcinoma metastasis(Xu et al. 2020). In our work, we found that COL7A1 was also overexpressed in several reports in Oncomine database. In order to further prove the results, we confirmed that COL7A1 was indeed highly expressed in LUSC through TCGA data in UALCAN and immunohistochemical experiments. Then we used the UALCAN database to analyze the expression pattern of COL7A1 in lung squamous cell carcinoma and confirmed that COL7A1 was up-regulated in different clinical classifications. In order to study the possible role of COL7A1 in LUCS, we first performed Oncomine co-expression analysis and found that COL7A1 was closely related to GPC1, SERPINB5, BNC1, PKP1, SOX15, PVRL1, FAT2, ANXA8L2, S1PR5, BNC1, DST, TRIM29, GJB5, IRF6, KRT17. In other studies, GPC1 was found to regulate PTEN/Akt/β-Catenin pathway promotes the invasive proliferation of Esophageal Squamous Cell Carcinoma (ESCC) cells(Li et al. 2019). Interestingly, hypermethylation of BNC1 promoter in tissues may cause liver cancer(Wu et al. 2016). PKP1 is an essential component of the desmosomes and PKP1 leads to lung squamous cell carcinoma by promoting the translation of MYC(Martin-Padron et al. 2020). SOX15 is a tumor suppressor in pancreatic cancer and esophageal cancer. It can play a potential role in regulating Wnt/β-catenin signaling(Moradi et al. 2017).

There are other studies that show that decrease of FAT2 caused by siRNA may lead to the invasion of squamous cell carcinoma(Matsui et al. 2008). In addition, we also studied the protein-protein interaction through the STRING database and found 10 proteins closely related to COL7A1, including MIA3, BMP1, ITGB3, ITGB1, ITGAV, LAMC2, LAMB3, P4HA2, ITGA2, TLL1. BMP1 activates transforming growth factor-β (TGF-β) by proteolysis and BMP signaling pathway play an important role in the occurrence and development of gastrointestinal tumors(Rafi et al. 2021). Hypoxia enhances the translation of ITGB3 in breast cancer cells and activates TGF-β signal transduction(Sesé et al. 2017). LAMC2 promotes tumor invasion and cell survival through the activation of phosphatidylinositol-3 kinase (PI3K) and Rac1(Marinkovich 2007). Finally, in order to confirm whether COL7A1 has clinical significance in patients with lung squamous cell carcinoma and study its impact on prognosis, we conducted Kaplan Meier plotter analysis and obtained the survival curves of different survival evaluation indexes of LUSC. It found that high expression of COL7A1 has a poor prognosis in patients with lung squamous cell carcinoma in different curves (FS, OS, PPS,).

In summary, COL7A1 expression is up-regulated in lung squamous cell carcinoma, and patients with low COL7A1 expression have a good prognosis. Besides, COL7A1 is closely related to various biomarkers and factors of cancer, some of which play a precise role in lung squamous cell carcinoma.

Data Availability Statement

All data for this study are from an open database and are publicly available.

Conflicts of Interest

The authors declare that they have no conflicts of interest regarding the publication of this article.

Authors Contributions

Conceived and designed the experiments: Weihao Song and Ling Li. Administrative support: Ling Li, Jinyu Zhang and Shuang Wang. Provision of study materials or patients: Ling Li and Shuang Wang. Performed the experiments: Weihao Song, Zhe Leng, Ran Lu, Chenglin Li and Xiaoran Ma. Data analysis and interpretation: Weihao Song, Tiantian Wang and Xihui Jia. Manuscript writing: Weihao Song. Final approval of manuscript: All authors. Weihao Song and Ling Li are co-first authors.

Funding

This work was supported by the National natural Science Foundation of China (82001754), Natural Science Foundation of Shandong Province (ZR2020MH416).

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No competing interests reported.

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Identification of COL7A1 as a prognostic biomarker in lung squamous cell carcinoma

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Abstract

Figures

Introduction

Materials And Methods

Oncomine Analysis

UALCAN Analysis

Immunohistochemistry and Antibody

STRING Analysis

Co-expressed Genes

GO annotation enrichment and KEGG pathway enrichment analysis

Survival Analysis

Results

COL7A1 expression in lung squamous cell carcinoma

Expression changes of COL7A1 in different clinical indexes of LUSC

Association of COL7A1 expression with prognosis in LUSC patients

Gene co-expression analysis and protein-protein interaction

GO and KEGG enrichment

Discussion

Conclusion

Declarations

References

Additional Declarations

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