NcRNAs-induced CAPZA1 associated with prognostic and immunological effects across Lung adenocarcinoma

doi:10.21203/rs.3.rs-1629783/v1

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NcRNAs-induced CAPZA1 associated with prognostic and immunological effects across Lung adenocarcinoma

https://doi.org/10.21203/rs.3.rs-1629783/v1

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Recently, extensive discoveries have suggested that the F-actin capping protein α1 subunit (CAPZA1) in various human tumors could elicit significantly important parts in regulating cell proliferation, metastasis and epithelial-mesenchymal transition. However, the immune-regulating role of CAPZA1 in the initiation and development of Lung adenocarcinoma (LUAD) remains incompletely clear. In our research, we firstly found that CAPZA1 serves as an oncogene in pan-cancers from TCGA data and higher CAPZA1 expression process unfavorably prognostic value in LUAD based on Starbase database and PrognoScan database. Then, in our analyses, lncRNAs AC026356.1 in LUAD acts as a competitive endogenous RNA (ceRNA) of miR-30d-5p, which might be the possible regulatory miRNA of CAPZA1 based on the Starbase database. Finally, we confirmed that CAPZA1 expression had a tightly positive correlation with immune infiltration cells, immune infiltration markers, TMB, MSI, immune score, stromal score, and immune checkpoints, indicating that CAPZA1 was a markedly reliable therapeutic target for immunological antitumor strategy. In conclusion, our investigations unveiled that CAPZA1 might function as an immune-associated biomarker in the development and treatment of LUAD, thereby acting as a promising prognostic and therapeutic target against LUAD.

LUAD

CAPZA1

ceRNA

prognosis

immunotherapy

Lung cancer (LC) has gradually become a leading cause of cancer-related morbidity and mortality worldwide among men and women ^{1; 2}. Lung adenocarcinoma (LUAD) accounts for over 40% of lung cancer, with the most common subtype of lung cancer³. Despite advances in therapeutic strategies such as surgical techniques, radiotherapy, and chemotherapy, the survival of patients with LUAD is still unfavorable ⁴. Immunotherapy has been a promising and effective treatment strategy for multiple cancers ^5–7, including LUAD ⁸. However, there are some limitations regarding immune checkpoint inhibitors to this study: over half of the LUAD patients are not markedly sensitive to PD-1/PD-L1 antitumor immunotherapy, indicating the existence of additional immunotherapeutic biomarkers in the LUAD tumor microenvironment ⁹. Therefore, we aim to propose identifying immune-associated prognostic biomarkers to conquer LUAD for timely detection, early diagnosis, prognosis, and treatment.

F-actin capping protein α1 subunit (CAPZA1) belongs to Capping protein (CP) which is a family of the actin filament (F-actin) that is a critical component of the cytoskeleton, and the dynamic remodeling of these filaments provides the impetus for cell invasion and migration^10–13. Recent discoveries have suggested that CAPZA1 in various human tumors could regulate cell proliferation, metastasis and epithelial-mesenchymal transition ^{14; 15} and elevated CAPZA1 is closely linked to unfavorable prognosis in gastric cancer ¹⁶. For instance, PIM1 phosphorylated CAPZA1 and was responsible for increasing prostate cancer adhesion and migration in vitro ¹⁷. Additionally, during the immune process, the actin cytoskeleton plays a pivotal role in controlling B cell antigen uptake, polarization, presentation, and T-lymphocyte activation and effector functions in the tumor microenvironment (TEM) ^{18; 19}. To the best of our knowledge, the immune-regulating role of CAPZA1 in LUAD development remains incompletely understood.

This current study investigated the expression profiling and prognostic value of CAPZA1 in pan-caners based on several databases. Then, ncRNAs, containing miRNAs and lncRNAs, participated in the regulation of CAPZA1 in LUAD was determined. High CAPZA1 levels in LUAD were also associated with immune cell infiltration and immune checkpoints, suggesting that ncRNAs-induced CAPZA1 is referred to be an immune-related biomarker with a worse impact on clinical outcomes.

2.1 Data collection and processing

The mRNA expression data, somatic mutation data of the LUAD in The Cancer Genome Atlas (TCGA) database were acquired using UCSC Xena (https://xena.ucsc.edu/) ²⁰. MSI data download from the research of Russell Bonneville ²¹.

2.2 StarBase online database

The StarBase database (http://starbase.sysu.edu.cn/) ²² was employed to identify the differentially expressed CAPZA1 and its prognostic value in many types of cancers. The expression of CAPZA1 is presented by FPKM (fragments per kilobase of transcript sequence per millions of base pairs sequenced). Firstly, the StarBase database involving PITA, RNA22, miRmap, microT, miRanda, PicTar, and TargetScan was employed to predict potential miRNAs that directly bond to CAPZA1 upstream in LUAD and speculate their differential expression and OS. Next, we forecasted potential hsa-miR-30d-5p-modulated lncRNAs in LUAD and analyzed differential expression level and prognosis of miRNAs screened. Finally, the starBase database was also used to examine the miR-30d-5p-CAPZA1, miR-30d-5p-AC026356.1, and AC026356.1-CAPZA1 interactions. P < 0.05 was treated as the significance threshold for all statistical analyses.

2.3 Survival analysis

The CAPZA1 survival analysis of CAPZA1 expression in LUAD was validated through the PrognoScan database (http://www.abren.net/PrognoScan/) ²³. Corrected P-value < 0.05 was regarded as a statistically significant difference.

2.4 Immunity analysis

Additionally, we applied the TIMER online database (https://cistrome.shinyapps.io/timer/) ²⁴, a comprehensive resource for systematic analysis of tumor immune infiltrates, immune infiltrates biomarkers, and immune systems checkpoint across LUAD into CAPZA1- associated the abundance of the immune response.

2.5 Correlation between CAPZA1 and Immune Characteristics

Recent studies have shown that Tumor mutational burden (TMB) refers to predict the response to the clinical efficacy of anti-PD1/PD-L1 treatment ²⁵. Microsatellite instability (MSI) ²⁶ has also been referred to as an indispensable biomarker in the TME. To further evaluate CAPZA1 in LUAD immunity, we examined the link between CAPZA1 expression and MSI, TMB. Finally, ImmuneScore and StromalScore analyses were carried out via the "estimate" R package.

2.6 Gene set enrichment analysis.

GSEA ²⁷ (version 3.0, http://www.broadinstitute.org/gsea/index.jsp) has been utilized for evaluating gene sets or biological pathways, which varied significantly between CAPZA1 with high and low-expression level groups. In this study, following settings were used: 500 was the maximum size of gene set, while 15 was the minimum size of gene set, 1,000 was the number of permutations, along with improved gene sets with FDR (false discovery rate) q-val < 0.05 have been measured significant.

3.1 CAPZA1 mRNA expression in pan-cancers

CAPZA1 mRNA levels from 33 cancer types in TCGA were applied in TIMER. The results indicated that the expression of CAPZA1 was relatively higher in 13 cancers such as BLCA, BRCA, CHOL, ESCA, HNSC, KIRC, KIRP, LIHC, LUAD, LUSC, STAD, THCA, UCEC, while the deletion of CAPZA1 was in KICH and SKCM (Figure1A). We further utilized the Starbase database to verify whether the CAPZA1 expression is overexpressed in multiple tumor tissues, as Figure1B-M, CAPZA1 mRNA expression in above 13 types of cancer was still upregulated.

3.2 Prognostic potential of CAPZA1in pan-cancers

Firstly, the Starbase database was employed to explore the prognosis of CAPZA1 in pan-cancers data downloaded from TCGA. The result indicated that CAPZA1 at high expression afforded worse OS in KIRC, KIRP, LUAD, and LIHC (Figure2A). Then, the fact that patients with high CAPZA1 expression had unfavorable long-term prognosis in LUAD was also validated in the PrognoScan database (Table 1). These findings indicated that overexpressed CAPZA1 might be a worse prognostic marker in LUAD.

3.3 Prediction and analysis of upstream miRNAs of CAPZA1

Noncoding RNAs (ncRNAs) are derived through the genome that fails to translate to proteins but regulates gene expression in the field of cancers, including miRNAs and lncRNAs ^{28; 29}. Thus, we aim to analyze the role of ncRNAs in the regulation of CAPZA1. Initially, we found 16 potential miRNAs that directly bond to CAPZA1 as its upstream (Figure 3A, B supplementary Table 1). As is well known, miRNAs could negatively modulate the expression of target genes via causing their cleavage or translational repression ³⁰. As expected, CAPZA1 reversely correlated with hsa-miR-30a-5p, hsa-miR-30c-5p, hsa-miR-27b-3p, hsa-miR-488-3p and hsa-miR-30d-5 in LUAD in the basis of correlation analysis (Figure 3B, P<0.05). We then examined the expression and prognosis of the above miRNA and found that only the hsa-miR-30d-5 in LUAD was at a low level, and its downregulation harbored a better life for patients(Figure 3C, D, E, P<0.05). These findings unveil that CAPZA1 might be the most potential targeted mRNA of hsa-miR-30d-5 in LUAD.

3.4 Screen of miR-30d-5p-induced upstream lncRNA

Subsequently, we forecasted potential upstream lncRNAs of hsa-miR-30d-5p in LUAD through the starBase database and observed nine possible lncRNAs (Supplementary Table 2 and Supplementary Figure1). Based on the competitive endogenous RNA (ceRNA) hypothesis, LncRNA sponges various miRNAs to inhibit its expression and reduce the regulatory effect on target mRNA ³¹. Consequently, only AC026356.1 in LUAD was at high activity than normal samples, and higher AC026356.1 was reciprocally linked to favorable patients’ OS among all the nine lncRNAs (Figure 4A-P). AC026356.1 lncRNA was positively relevant to CAPZA1 expression whereas negative with hsa-miR-30d-5p using starBase database (Table2 and Table3). To this end, AC026356.1 in LUAD might be most likely to upstream lncRNAs of the hsa-miR-30d-5p-CAPZA1 axis (Figure5).

3.5 CAPZA1-associated immune infiltration assessment in LUAD

TME harbors comprehensive infiltrating immune cells, which contributes to influencing the development of cancers, so we investigated the relationship between CAPZA1 expression and immune infiltration. As presented in Figure6A, the CAPZA1 expression level in LUAD was statistically positively related to macrophages, CD4+ T cells, CD8+ T cells, dendritic cells, and Neutrophil and purity, whereas the reciprocal association with B cells. Moreover, copy numbers of CAPZA1 were also closely related to immune cell infiltration (Figure6B).

3.6 Correlation analysis of CAPZA1 as well as AC026356.1 and immune checkpoints in LUAD

PD1/PD-L1 and CTLA-4 have proven to be well-known immune checkpoints that play instrumental roles in cancer treatment modalities due to immune surveillance and escape. To ascertain the role of the immune response of CAPZA1 as well as AC026356.1 in LUAD , we utilized TIMER data to analyze the link between CAPZA1 and these well-acknowledged immune checkpoints. Indeed, both CAPZA1 andAC026356.1 harbored significant effect on PD1, PD-L1, and CTLA-4 expression in LUAD, respectively (Figure7A-F), demonstrating that CAPZA1 as well as AC026356.1 can mediate tumorigenesis and progression by regulating tumor immune escape in LUAD.

3.7 The correlation of CAPZA1 with immunotherapy and potential mechanisms

We further confirmed that CAPZA1 in LUAD was significantly positively correlated with the TMB, MSI, immune score, stromal score and estimateScores (Figure8A-E). GSEA revealed that CAPZA1 might be involved in cancer-related critical pathways such as CELL CYCLE, P53 SIGNALING PATHWAY, MISMATCH REPAIR, NOD-LIKE RECEPTOR SIGNALING PATHWAY and TOLL LIKE RECEPTOR SIGNALING PATHWAY (Figure8F).

LUAD is one of the significant invasive diseases limiting the life span of humans ^32–34. Identifying the molecular mechanisms underlying LUAD carcinogenesis is becoming increasingly instrumental in searching for novel therapeutic targets and biomarkers. Previous studies have confirmed that CAPZA1 elicited pivotal roles in regulating the onset and development of human cancers ^{35; 36}. The role of CAPZA1 in LUAD, however, remains incompletely known and needs to take further study.

Our study first examined that CAPZA1 was significantly overexpressed at mRNA levels in 13 tumors compared with normal tissues, which was validated in the Starbase database. Moreover, survival and prognosis analysis displayed that higher CAPZA1 correlated with worse survival in KIRC, KIRP, LUAD, and LIHC using Starbase database, and only prognosis of CAPZA1 in LUAD had been validated in the PrognoScan database, which might shed light on novel targets for LUAD individualized treatment.

Mechanisms related to ceRNA are modulated by ncRNAs with direct or indirect effects, including gene expression regulation ³⁷. Our study used the Starbase database to find possible miRNAs that interact with CAPZA1 RNA binding proteins, thereby modulating CAPZA1 mRNA stability. The result revealed that 16 miRNAs were finally found. Further analysis shows that only hsa-miR-30d-5p in LUAD was screened since it was low, and its downregulation harbored a better life of patients. Most of the researches related to this miRNA has proved to be tumor-suppressive in many cancers, such as prostate cancer ³⁸, renal cell carcinoma (RCC) ³⁹, non-small cell lung cancer (NSCLC) ⁴⁰, esophageal squamous cell carcinoma (ESCC) ⁴¹, and gallbladder ⁴². For instance, down-regulated miR-30d-5p has been linked to favorable clinical outcomes in patients with RCC, and overexpression of miR-30d-5p attenuates RCC cell lines proliferation and cell-cycle G1/S transition and facilitated apoptosis, which is denoted as tumor-suppressor ³⁹. Overall, CAPZA1 might be the most potential targeted mRNA of hsa-miR-30d-5 in LUAD.

Recently, lncRNAs have been considered as miRNA sponges to contribute to the regulation of cancers ⁴³. Based on this, 9 possible lncRNAs in LUAD function as the upstream of the hsa-miR-30d-5-CAPZA1 axis. Following survival analysis and correlation analysis, only AC026356.1 was at high activity than normal samples and higher AC026356.1 was reciprocally linked to favorable patients’ OS among all these lncRNAs. More importantly, AC026356.1 lncRNA was positively relevant to CAPZA1 expression whereas negative with hsa-miR-30d-5p, uncovering that AC026356.1 is most likely upstream lncRNAs of hsa-miR-30d-5p-CAPZA1 axis.

Extensive evidence has proved that the tumor-infiltrating immune cells exert a crucial function on patients' prognosis and immunotherapy ⁴⁴. For example, activating tumor-infiltrating CD8 T cells were able to contribute to antitumor responses ⁴³. In our analysis, CAPZA1 in LUAD was positively relevant to the infiltration of most immune cells, especially for macrophages, CD4 + T cells, CD8 + T cells, dendritic cells, and Neutrophil and purity, which is also validated based on some immune infiltration markers. Also, we further confirmed that CAPZA1 in LUAD was significantly positively correlated with the TMB, MSI, immune score and stromal score, indicating that CAPZA1 could participate in regulating immune infiltration function in LUAD. Apart from this, immunotherapy, mainly represented by immune checkpoint inhibitors (ICIs), has shown promising efficacy in treating many types of cancers ⁴⁵. Thus, the link immune checkpoints like PD1, PD-L1, and CTLA-4 with CAPZA1 were assessed in LUAD. Similarly, this correlation had the same trend, indicating that CAPZA1 might serve as a new tumor immunotherapy target in LUAD.

Nevertheless, some restrictions are supposed to be highlighted in our investigations. Firstly, considering tissue specificity, we fail to enable our conclusions to replant to other tumors. Next, we need to validate the roles of CAPZA1 in LUAD on antitumor immunotherapy and tumor immunity based on more basic experiments. Finally, it is imperative to gather more robust data or samples of LUAD due to the lack of available public datasets.

For the first time, collectively, we comprehensively determine the CAPZA1 serve as an oncogene in pan-cancers and higher CAPZA1 expression process unfavorably prognostic value in LUAD based on Starbase database and PrognoScan database. Our findings also uncovered that CAPZA1 might play an essential role in tumor immunity during the development of LUAD, such as immune infiltration cells, immune infiltration markers, TMB, MSI, immune score, stromal score, and immune checkpoints, and maybe a reliable therapeutic target for immunological antitumor strategy.

Funding

The author(s) received no financial support for the research, author-ship, and/or publication of this article.

Authors’ Note

The project was designed and conceived by Ting-ting Qin. Ting-ting Qin analyzed the data. Ting-ting Qin, Na Li and Lan Liwrote the manuscript. Qi-bin Song guided the execution of the study and revised the paper. All authors have read and approved the final version of this manuscript.

Acknowledgments

We appreciatively thank the UCSC, TCGA, StarBase, TIMER, PrognoScan databases for the availability of the data.

Ethical Statement

Our study did not require an ethical board approval because it did not contain human or animal trials.

Declaration of Competing interest

The authors declare that they have no competing interests, and all authors should confirm its accuracy.

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Table1 The Prognostic value of CAPZA1 in lung adenocarcinoma in PrognoScan.

GENE_NAME	DATASET	CANCER TYPE	ENDPOINT	N	COX P-VALUE	ln(HR)	HR [95% CI-low CI-upp]
CAPZA1	GSE31210	Adenocarcinoma	Relapse Free Survival	204	8.27E-05	3.90283	49.54 [7.10 - 345.90]
CAPZA1	GSE13213	Adenocarcinoma	Overall Survival	117	0.000201	0.742359	2.10 [1.42 - 3.11]
CAPZA1	jacob-00182-MSK	Adenocarcinoma	Overall Survival	104	0.06556	2.05522	7.81 [0.88 - 69.60]
CAPZA1	GSE31210	Adenocarcinoma	Overall Survival	204	0.001298	4.45077	85.69 [5.69 - 1290.75]
CAPZA1	GSE13213	Adenocarcinoma	Overall Survival	117	0.03585	0.534665	1.71 [1.04 - 2.81]

Table2:The correlation between mir and lncRNA in lung adenocarcinoma.

miRNA	LncRNA	R-value	P-value
hsa-miR-30d-5p	LINC01133	-0.121	0.00595
hsa-miR-30d-5p	LINC02535	-0.128	0.00371
hsa-miR-30d-5p	AL024507.2	-0.293	1.29E-11
hsa-miR-30d-5p	LINC00707	-0.144	0.0011
hsa-miR-30d-5p	AL139125.2	-0.061	0.168
hsa-miR-30d-5p	AC026356.1	-0.299	4.71E-12
hsa-miR-30d-5p	AL049840.4	0.061	0.17
hsa-miR-30d-5p	GACAT2	-0.136	0.00198

Table3: The correlation between lncRNA and CAPZA1 in lung adenocarcinoma.

LncRNA	GENE	R-value	P-value
LINC01133	CAPZA1	0.072	9.94E-02
LINC02535	CAPZA1	0.072	9.92E-02
AL024507.2	CAPZA1	0.218	4.27E-07
LINC00707	CAPZA1	0.034	4.38E-01
AL139125.2	CAPZA1	0.011	7.93E-01
AC026356.1	CAPZA1	0.317	1.01E-13
AL049840.4	CAPZA1	-0.129	3.14E-03
GACAT2	CAPZA1	0.24	2.52E-08

No competing interests reported.

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NcRNAs-induced CAPZA1 associated with prognostic and immunological effects across Lung adenocarcinoma

Status:

Version 1

Abstract

Figures

1.0 Introduction

2.0 Material And Methods

2.1 Data collection and processing

2.2 StarBase online database

2.3 Survival analysis

2.4 Immunity analysis

2.5 Correlation between CAPZA1 and Immune Characteristics

2.6 Gene set enrichment analysis.

3.0 Results

3.1 CAPZA1 mRNA expression in pan-cancers

3.2 Prognostic potential of CAPZA1in pan-cancers

3.3 Prediction and analysis of upstream miRNAs of CAPZA1

3.4 Screen of miR-30d-5p-induced upstream lncRNA

3.5 CAPZA1-associated immune infiltration assessment in LUAD

3.6 Correlation analysis of CAPZA1 as well as AC026356.1 and immune checkpoints in LUAD

3.7 The correlation of CAPZA1 with immunotherapy and potential mechanisms

4.0 Discussion

Declarations

Funding

Authors’ Note

Acknowledgments

Ethical Statement

Declaration of Competing interest

References

Tables

Additional Declarations

Supplementary Files

Status:

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