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. 2020 May 22;146(8):1993–2006. doi: 10.1007/s00432-020-03259-x

Comprehensive analysis of the HOXA gene family identifies HOXA13 as a novel oncogenic gene in kidney renal clear cell carcinoma

Yuanbo Cui 1,2,✉,#, Ming Yan 3,#, Chunyan Zhang 4, Jinhui Xue 5, Quanwu Zhang 5, Shanshan Ma 2, Fangxia Guan 2,✉, Wei Cao 1,✉
PMCID: PMC11804755  PMID: 32444962

Abstract

Objectives

Kidney renal clear cell carcinoma (KIRC) is one of the most common lethal cancers in the human urogenital system. As members of the Homeobox (HOX) family, Homeobox-A (HOXA) cluster genes have been reported to be involved in the development of many cancer types. However, the expression and clinical significance of HOXA genes in KIRC remain largely unknown.

Materials and methods

In this study, we comprehensively analyzed the mRNA expression and prognostic values of HOXA genes in KIRC using The Cancer Genome Atlas (TCGA) analysis databases online. Colony formation assay, flow cytometry and Western blot were used to detect cell proliferation, apoptosis, cell cycle, and protein level of the indicated gene.

Results

We found that the HOXA genes were differentially expressed in KIRC tissues when compared with normal tissues. The expression of HOXA4 and HOXA13 were significantly up-regulated, while HOXA7 and HOXA11 were down-regulated in KIRC. High mRNA levels of HOXA2, HOXA3 and HOXA13, and low level of HOXA7 predicted poor overall survival (OS) of KIRC patients. High mRNA level of HOXA13 further indicated a poor disease-free survival (DFS) of KIRC patients. Functionally, knockdown of HOXA13 significantly suppressed cell proliferation of KIRC in vitro, increased the protein level of p53 and decreased the protein level of cyclin D1 in KIRC cells. Over-expression of HOXA13 had the opposite effects on KIRC cells.

Conclusion

Collectively, our findings suggest that HOXA13 functions as a novel oncogene in KIRC and may be a potential biomarker for this malignancy.

Electronic supplementary material

The online version of this article (10.1007/s00432-020-03259-x) contains supplementary material, which is available to authorized users.

Keywords: Kidney renal clear cell carcinoma, Homeobox-A cluster genes, HOXA13, Oncogene, Prognosis

Introduction

Kidney renal clear cell carcinoma (KIRC), a common genitourinary malignancy, is the main subtype and accounts for about 80% of all renal cell carcinoma (RCC) cases. Patients with KIRC have higher rates of tumor recurrence and metastasis when compared to patients with other subtypes of RCC (Dong et al. 2019; Siegel et al. 2017). According to the Cancer Statistics, approximately 140,000 cases per year of KIRC are estimated to die worldwide (Siegel et al. 2017). Although several treatment strategies including chemoradiotherapy, INF-α therapy and targeted therapy (sorafenib, sunitinib) have been implemented in clinical practice, the prognosis of KIRC patients remains unsatisfactory (Siegel et al. 2017; Huang et al. 2019). Therefore, exploring novel effective biomarkers will contribute to improving the treatment and prognosis of KIRC.

Homeobox (HOX) genes, a large group of evolutionary conserved family, are crucial transcriptional regulators that play diverse roles from embryogenesis to tumorigenesis. In humans, the HOX family contains four gene clusters termed HOXA, HOXB, HOXC and HOXD, which are located on different chromosomes (7p15, 17q21, 12q13 and 2q31) (Bhatlekar et al. 2018). HOXA cluster genes include 11 members named as HOXA1, HOXA2, HOXA3, HOXA4, HOXA5, HOXA6, HOXA7, HOXA9, HOXA10, HOXA11 and HOXA13. Recent evidence has shown that HOXA genes participated in the initiation and development of various human malignancies (Bhatlekar et al. 2014,2018; Wang et al. 2016). For example, HOXA1 is up-regulated in breast cancer tissues and is associated with patient prognosis (Liu et al. 2019). HOXA3 promotes colon cancer progression by regulating EGFR/Ras/Raf/MEK/ERK pathway (Zhang et al. 2018). HOXA5 can cooperate with p53 to inhibit cell invasion and serve as a possible prognostic factor in non-small cell lung cancer (Chang et al. 2017). Up-regulated HOXA13 promotes gastric cancer progression while high HOXA10 exerts tumor suppressive role in prostate cancer (Qin et al. 2019; Hatanaka et al. 2019). These findings imply that HOXA genes may contribute to carcinogenesis and have potential clinical application values. However, to date, little is known about the expression profile and clinical significance of HOXA genes in KIRC.

As far as we know, comprehensive bioinformatics analysis has not been reported to explore the expression and clinical significance of HOXA genes in KIRC. In this study, several members of the HOXA genes were found to have substantial clinical values in KIRC. The findings of this study highlight the crucial role of HOXA13 in the progression and prognosis of KIRC.

Materials and methods

The Cancer Genome Atlas (TCGA) data analysis

Four online TCGA analysis databases (GEPIA, starBase v3.0, UALCAN and Kaplan–Meier Plotter) were used to observe the expression and prognostic value of 11 members of HOXA genes in KIRC. GEPIA (Tang et al. 2017) was used to observe the expression and prognosis (OS and DFS) of HOXA genes in KIRC. The starBase v3.0 (Li et al. 2014) tool was utilized to examine the expression and prognosis (OS) of HOXA genes in KIRC. UALCAN (Chandrashekar et al. 2017) was used to observe the expression of HOXA genes in KIRC. Kaplan–Meier Plotter (Nagy et al. 2018) was utilized to determine the relationship between HOXA genes expression and patient prognosis (OS and DFS) in KIRC. The co-expressed genes of HOXA13 in KIRC were obtained from the TCGA database LinkedOmics (Vasaikar et al. 2018). Gene Set Enrichment Analysis (GSEA) of HOXA13-related genes in KIRC based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) was analyzed by the WebGestalt (Liao et al. 2019).

Cell culture and siRNA transfection

Three human KIRC cell lines (786-O, Caki-1 and A498) and one normal renal tubular epithelial cell line (HK-2) were previously obtained from Procell Life Science & Technology (China). 786-O, Caki-1 and A498 were cultured in RPMI medium supplemented with 10% FBS (Gibco, USA) (37 ℃, 5% CO2). HK-2 was maintained in DMEM medium supplemented with 10% FBS (Gibco, USA) (37 ℃, 5% CO2). The INTERFERin reagent (Polyplus Transfection, France) was used to transfect siRNAs or plasmids into Caki-1 cells.

Quantitative real-time PCR (qRT-PCR)The qRT-PCR analysis was utilized to examine the transcriptional level of HOXA13 in KIRC tissues and cells. In brief, the Trizol reagent (Invitrogen, USA) and cDNA synthesis kit (DBI, Germany) were used for RNA isolation and reverse transcription, respectively. Then, qRT-PCR analysis was performed using the SYBRGreen qRT-PCR kit (DBI, Germany) and the Fast 7500 system (ABI, USA). The primers are shown as follows:

HOXA13-forward: 5′-CGCTTCAGAACTCGTTGCTTTGC-3′;

reverse: 5′-CGGAAGAACTGGCAGTCTTTACCT3′.

GAPDH-forward: 5′-TCAGAGGACGGCATGAGACTTA-3′;

reverse: 5′-AGCAGGACCCAGGTGTCATT3′.

Colony formation assay

Cell proliferative ability of Caki-1 after transfected with siRNAs or pcDNA-HOXA13 plasmids was examined by the colony formation assay. Briefly, transfected cells were seeded into 6-well plates (1000 cells per well) and cultured in a cell incubator for about 7 days with medium replacement. Then, cell colonies were fixed in methanol, stained with crystal violet solution and calculated by the Image J software.Flow cytometry

Cell apoptosis and cell cycle of Caki-1 transfected with siRNAs or pcDNA-HOXA13 plasmids were detected by flow cytometry. Briefly, cells were seeded into 6-well plates. Forty-eight hours after transfection, cells were subjected to apoptosis and cell cycle detection by using the Annexin V-FITC/PI kit (7sea biotech, China) and PI kit (7sea biotech, China), respectively. The procedures were following the user’s instructions.

Western blot analysis

Total protein of each sample was obtained by using RIPA lysis buffer. After denaturation, an equal amount of protein from each sample was used to carry out SDS-PAGE and PVDF membrane transfer. Then, the membranes were blocked in 5% skim milk and incubated with diluted primary antibodies (GAPDH, Abcam, USA; p53, Santa, USA; Cyclin D1, Santa, USA) and HRP-conjugated second antibody. Finally, the immunoreactive protein bands were detected by ECL reagent and the imaging system (Bio-Rad, USA).

Statistical analysis

For the expression of HOXA genes in cancer, fold change greater than 2 and p value less than 0.05 were considered as significant difference. For the prognostic value of HOXA genes in cancer, patients in each database were divided into two groups (low and high) according to the median level of each HOXA gene in KIRC tissues, and log-rank p value less than 0.05 was considered to be statistically significant. Data of functional experiments are presented as mean ± SD. SPSS 19.0 was used for statistical analysis (Student’s t-test). A p value less than 0.05 was considered to be statistically significant.

Results

The transcriptional level of each member of HOXA genes in KIRC

Three online TCGA analysis tools (GEPIA, UALCAN and starBase v3.0) were used to analyze the transcriptional levels of HOXA genes in patients with KIRC. Data from GEPIA showed that the mRNA levels of HOXA7 (p < 0.05) and HOXA11 (p < 0.05) were significantly down-regulated, while HOXA4 (p < 0.05) and HOXA13 (p < 0.05) were obviously up-regulated in KIRC tissues (n = 523) as compared with the adjacent normal tissues (n = 100) (Fig. 1). There were no significant changes in mRNA levels of HOXA1, HOXA2, HOXA3, HOXA5, HOXA6, HOXA9 and HOXA10 between KIRC tissues and normal tissues. Data from UALCAN displayed that the mRNA levels of HOXA2 (p = 1.72E-7), HOXA5 (p < 1.0E-12), HOXA6 (p = 1.0E-12), HOXA7 (p < 1.0E-12), HOXA9 (p < 1.0E-12) and HOXA11 (p = 1.5E-8) were evidently down-regulated, while HOXA3 (p = 3.8E-8), HOXA4 (p < 1.0E-12) and HOXA13 (p = 1.4E-6) were obviously up-regulated in KIRC tissues (n = 533) as compared with the adjacent normal tissues (n = 72) (Fig. 2). There were no significant changes in mRNA levels of HOXA1 and HOXA10 between KIRC tissues and normal tissues. Data from starBase v3.0 (Fig. 3) showed the same trend of HOXA genes expression between KIRC (n = 535) and normal (n = 72) tissues with the results from UALCAN. A comparison of these three datasets revealed that HOXA4 and HOXA13 were significantly increased, while HOXA7 and HOXA11 were dramatically decreased in KIRC tissues (Fig. 9a).

Fig. 1.

Fig. 1

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The transcriptional levels of HOXA genes in KIRC were analyzed by GEPIA

Fig. 2.

Fig. 2

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The transcriptional levels of HOXA genes in KIRC were analyzed by UALCAN

Fig. 3.

Fig. 3

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The transcriptional levels of HOXA genes in KIRC were analyzed by starBase v3.0

Fig. 9.

Fig. 9

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Data comparison was shown as Venn diagram (a) Data comparison of Fig. 1, Fig. 2 and Fig. 3 revealed four dysregulated HOXA members (HOXA4, HOXA13, HOXA7 and HOXA11) in KIRC. (b) Data comparison of Fig. 4, Fig. 5 and Fig. 6 revealed that four HOXA members (HOXA2, HOXA3, HOXA13 and HOXA7) were closely related to patient OS in KIRC. (c) Data comparison of Fig. 7 and Fig. 8 revealed that HOXA13 was closely related to patient DFS in KIRC. (d) Data comparison of Fig. 4, Fig. 5, Fig. 6, Fig. 7 and Fig. 8 revealed that HOXA13 was closely related to both OS and DFS of KIRC patients

In this database, HOXA4 and HOXA13 were significantly up-regulated, while HOXA7 and HOXA11 were down-regulated in KIRC as compared to the normal tissues. The red bar graph refers to tumor tissue (n = 523) and the blue bar graph refers to normal tissue (n = 100), *p < 0.05.

In this database, HOXA3, HOXA4 and HOXA13 were significantly up-regulated, while HOXA2, HOXA5, HOXA6, HOXA7 and HOXA11 were down-regulated in KIRC as compared to the normal tissues. The red bar graph refers to tumor tissue (n = 533) and the blue bar graph refers to normal tissue (n = 72), *p < 0.05.

In this database, HOXA3, HOXA4 and HOXA13 were significantly up-regulated, while HOXA2, HOXA5, HOXA6, HOXA7 and HOXA11 were down-regulated in KIRC as compared to the normal tissues. The orange bar graph refers to tumor tissue (n = 535) and the purple bar graph refers to normal tissue (n = 72), *p < 0.05.

The prognostic values of HOXA genes for OS in KIRC patients

Three online TCGA analysis tools (GEPIA, starBase v3.0 and Kaplan–Meier Plotter) were used to analyze the relationship between each HOXA gene expression and patient OS in KIRC. Data from GEPIA showed that high expression of HOXA2 (p = 3.5E-6), HOXA3 (p = 2.3E-4) and HOXA13 (p = 4.8E-6), while low expression of HOXA4 (p = 0.01), HOXA5 (p = 0.006), HOXA6 (p = 0.0067) and HOXA7 (p = 0.0036) independently predicted poor OS of patients with KIRC (Fig. 4). Data from starBase v3.0 displayed that high expression of HOXA1 (p = 0.0011), HOXA2 (p = 2.7E-8), HOXA3 (p = 1.6E-4), HOXA10 (p = 0.035), HOXA11 (p = 0.0097) and HOXA13 (p = 8.5E-7), while low expression of HOXA7 (p = 0.041) independently predicted poor OS of patients with KIRC (Fig. 5). Data from Kaplan–Meier Plotter indicated that high expression of HOXA1 (p = 4.1E-4), HOXA2 (p = 2.3E-8), HOXA3 (p = 5.4E-5), HOXA11 (p = 0.013) and HOXA13 (p = 3.7E-6), while low expression of HOXA7 (p = 0.025) independently predicted poor OS of patients with KIRC (Fig. 6). Comparison of these three datasets revealed that high expression of HOXA2, HOXA3 and HOXA13, while low expression of HOXA7 independently predicted poor OS of patients with KIRC (Fig. 9b).

Fig. 4.

Fig. 4

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The OS prognostic values of HOXA genes in KIRC were analyzed by GEPIA

Fig. 5.

Fig. 5

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The OS prognostic values of HOXA genes in KIRC were analyzed by starBase v3.0

Fig. 6.

Fig. 6

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The OS prognostic values of HOXA genes in KIRC were analyzed by Kaplan–Meier Plotter

Seven members (HOXA2, HOXA3, HOXA4, HOXA5, HOXA6, HOXA7 and HOXA13) were found to be significantly associated with patient OS in KIRC. Up-regulation of HOXA2, HOXA3 and HOXA13 was significantly associated with poor patient OS, while down-regulation of HOXA4, HOXA5, HOXA6 and HOXA7 was correlated with poor patient OS in KIRC. The red line refers to high gene expression and the blue line refers to low gene expression.

Seven members (HOXA1, HOXA2, HOXA3, HOXA7, HOXA10, HOXA11 and HOXA13) were found to be significantly associated with patient OS in KIRC. Up-regulation of HOXA1, HOXA2, HOXA3, HOXA10, HOXA11 and HOXA13 was significantly associated with poor patient OS, while down-regulation of HOXA7 was correlated with poor patient OS in KIRC. The green line refers to high gene expression and the brown line refers to low gene expression.

Six members (HOXA1, HOXA2, HOXA3, HOXA7, HOXA11 and HOXA13) were found to be significantly associated with patient OS in KIRC. Up-regulation of HOXA1, HOXA2, HOXA3, HOXA11 and HOXA13 was significantly associated with poor patient OS, while down-regulation of HOXA7 was correlated with poor patient OS in KIRC. The red line refers to high gene expression and the black line refers to low gene expression.

The prognostic values of HOXA genes for DFS in KIRC patients

Two online TCGA analysis tools (GEPIA and Kaplan–Meier Plotter) were used to analyze the relationship between each HOXA gene expression and patient DFS in KIRC. Data from GEPIA showed that high expression of HOXA1 (p = 0.037), HOXA2 (p = 0.023), HOXA11 (p = 0.038) and HOXA13 (p = 9.3E-7) independently predicted poor DFS of patients with KIRC (Fig. 7). Data from Kaplan–Meier Plotter indicated that high expression of HOXA5 (p = 0.046) and HOXA13 (p = 0.021) independently predicted poor DFS of patients with KIRC (Fig. 8). A comparison of these two datasets revealed that high expression of HOXA13 predicted poor DFS of patients with KIRC (Fig. 9c). Next, we compared the survival data from five datasets (Figs. 4, 5, 6, 7 and 8), and found that only HOXA13 was closely associated with the OS and DFS of KIRC patients. High mRNA level of HOXA13 predicts unfavorable OS and DFS for patients with KIRC (Fig. 9d).

Fig. 7.

Fig. 7

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The DFS prognostic values of HOXA genes in KIRC were analyzed by GEPIA

Fig. 8.

Fig. 8

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The DFS prognostic values of HOXA genes in KIRC were analyzed by Kaplan–Meier Plotter

Four members (HOXA1, HOXA2, HOXA11 and HOXA13) were found to be significantly associated with patient DFS in KIRC. Up-regulation of HOXA1, HOXA2, HOXA11 and HOXA13 was significantly associated with poor patient DFS in KIRC. The red line refers to high gene expression and the blue line refers to low gene expression.

Two members (HOXA5 and HOXA13) were found to be significantly associated with patient DFS in KIRC. Up-regulation of HOXA5 and HOXA13 was significantly associated with poor patient DFS in KIRC. The red line refers to high gene expression and the black line refers to low gene expression.

HOXA13 functions as an oncogene and promotes KIRC proliferation

Given that HOXA13 was significantly up-regulated in KIRC and closely correlated with patient prognosis including both OS and DFS, we speculated that HOXA13 might act as an oncogene in KIRC. To investigate the possible pathways mediated by HOXA13 in KIRC, we obtained the co-expressed genes of HOXA13 in KIRC from the LinkedOmics. The overall closely co-expressed genes of HOXA13 in KIRC were shown as a volcano plot (Fig. 10a). The top-50 positively and negatively co-expressed genes of HOXA13 in KIRC were shown as heat maps (Fig. 10b–c), respectively. GSEA based on the KEGG database was used to explore the potential pathways mediated by HOXA13 in KIRC. The results displayed that HOXA13 was primarily implicated in the regulation of biosynthesis of amino acids (p = 0, NES = 1.786), cell cycle (p = 0, NES = 1.627) and p53 signaling (p = 0, NES = 1.617) in KIRC (Fig. 10d–f). To confirm this, we observed the effects of HOXA13 knockdown or over-expression on KIRC proliferation in vitro. First, we examined the expression of HOXA13 in 8 pairs of KIRC tissues as well as in KIRC cell lines, and found that HOXA13 was highly expressed in KIRC tissues (p < 0.05) (Suppl. Fig. 1a) and cell lines (p < 0.05) (Suppl. Fig. 1b) as compared to the counterparts. Then, our results of functional experiments displayed that knockdown of HOXA13 significantly suppressed cell proliferation (p < 0.05) (Fig. 11a) might be through arresting cell cycle at the G0/G1 phase (p < 0.05) (Fig. 11b), rather than promoting apoptosis (Suppl. Fig. 1c). Results of Western blot indicated that down-regulation of HOXA13 increased the protein level of p53 and decreased the level of cell cycle-related protein cyclin D1 in Caki-1 cells (Fig. 11c). Over-expression of HOXA13 had the opposite effects on KIRC cells (p < 0.05) (Fig. 11a–c). These results suggest that HOXA13 promotes KIRC proliferation in vitro.

Fig. 10.

Fig. 10

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GSEA analysis of the HOXA13-related genes in KIRC. a The overall co-expressed genes of HOXA13 in KIRC were displayed as a volcano plot. b–c The positively (b) and negatively (c) co-expressed top-50 genes of HOXA13 in KIRC were shown as heat maps. d–f Three pathways (biosynthesis of amino acids, cell cycle and p53) were closely associated with HOXA13 in KIRC. NES refers to normalized enrichment score

Fig. 11.

Fig. 11

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The effects of HOXA13 knockdown or over-expression on cell proliferation in Caki-1 cells. a Colony formation assay was used to detect cell proliferation, *p < 0.05. b Flow cytometry was used to examine cell cycle, *p < 0.05. c Protein levels of p53 and cyclin D1 were determined by Western blot

Discussion

Accumulating evidence highlights the role of the HOXA gene family in the occurrence and progression of many human cancers. For instance, HOXA4 and HOXA10 contribute to the growth and metastasis of ovarian cancer (Idaikkadar et al. 2019). High expression of HOXA10 promotes cell proliferation, inhibits apoptosis and indicates worse OS of patients with gastric cancer (Song et al. 2019). Epigenetic silence of three HOXA genes (HOXA2, HOXA5 and HOXA5) may be important in the development of colorectal cancer (Li et al. 2019). However, the roles of all members of the HOXA gene family in KIRC remain unclear. Herein, we for the first time comprehensively analyzed the expression profile and clinical significance of HOXA genes based on the online TCGA analysis databases. We report that HOXA13 is a novel oncogene in KIRC based on bioinformatic analysis and experimental verification.

HOXA4, HOXA7, HOXA11 and HOXA13 have been proven to be involved in cancer-related biological processes. HOXA4 promotes cisplatin and gefitinib resistance in lung cancer (Yu et al. 2018; Tang et al. 2019). HOXA7 potentiates liver cancer metastasis via Snail signaling (Tang et al. 2016). HOXA11 functions as an oncogenic gene and is associated with tumor stage in renal cell carcinoma (Wang et al. 2017a, b). In this study, we explored the expression profile of HOXA genes in KIRC and found that HOXA4 and HOXA13 were significantly up-regulated, while HOXA7 and HOXA11 were dramatically down-regulated in KIRC. This implies that these four members of HOXA genes are potential candidates to be developed as early diagnostic or (and) therapeutic biomarkers for patients with KIRC.

Previous studies have shown that several HOXA genes have certain prognostic values in some cancer types. HOXA2 may serve as a prognostic parameter in non-small cell lung cancer and cervical cancer patients (Heller et al. 2013; Eoh et al. 2017). Up-regulated expression of HOXA3 is closely associated with a low OS rate of colon cancer patients (Zhang et al. 2018). In both prostate carcinoma and bladder cancer, HOXA13 is an unsatisfactory prognostic factor for patient survival (Dong et al. 2017; Hu et al. 2017). In this study, four members (HOXA2, HOXA3, HOXA13 and HOXA7) of the HOXA gene family were found to be closely associated with the OS of KIRC patients. These data indicate that these four members of HOXA genes are possible prognostic biomarkers for KIRC.

Considering that HOXA13 was significantly up-regulated in KIRC and significantly correlated with both OS and DFS in KIRC. We speculated that HOXA13 might be an important tumor driving gene in KIRC. Then, we performed KEGG signaling pathway analysis to explore the possible pathways mediated by HOXA13 in KIRC. Cell cycle and p53 signaling were found to be closely associated with HOXA13. P53, known as a suppressor in human cancer, is also involved in the development of KIRC (Wang et al. 2017a, b). In a previous study, it has been reported that HOXA13 contributed to gastric cancer progression in a p53-dependent way (Han et al. 2018). Thus, we speculated that HOXA13 might participate in KIRC through p53. To test this hypothesis, we performed some preliminary in vitro functional experiments, and found that HOXA13 promoted KIRC proliferation through cell cycle arrest. The protein level of p53 was found to be significantly increased after down-regulation of HOXA13 in KIRC cells.

In summary, this study comprehensively analyzed the expression and prognostic values of the HOXA gene family in KIRC using public online TCGA analysis databases. The study implies that some members of the HOXA genes may serve as clinical biomarkers for KIRC. Our findings highlight the important role of HOXA13 in the progression of KIRC and its crucial clinical significance in KIRC. Furthermore, we provide a preliminary understanding regarding the function and regulatory pathway mediated by HOXA13 in KIRC. Our study suggests that HOXA13 promoting KIRC progression may correlate with the p53 signaling pathway. The specific role of HOXA13 in KIRC needs to be further extensively explored.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (JPG 94 kb) (94.7KB, jpg)

Acknowledgements

We thank all participants for this manuscript.

Author contributions

YBC conceived and designed this study and wrote the manuscript. MY, CYZ, JHX, QWZ and SSM participated in functional experiments and data analysis. WC and FXG assisted in the revision of the manuscript and sample collection. All authors read the manuscript and approved it for publication.

Funding

This work was supported by the Key Scientific Research Projects of Institutions of Higher Learning in Henan Province (20A310018), the Provincial Co-construction Project of Medical Science and Technology in Henan (SB201903032), the Key Scientific and Technological Project in Henan Province (182102310328).

Compliance with ethical standards

Conflict of interest

The authors have declared that they have no competing interests.

Ethical approval

This study was approved by the Ethics Committee of the Zhengzhou Central Hospital Affiliated to Zhengzhou University.

Informed consent

Not applicable for this study.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Yuanbo Cui and Ming Yan contributed equally to this work.

Contributor Information

Yuanbo Cui, Email: cuiyuanbo18@126.com.

Fangxia Guan, Email: fxguan@126.com.

Wei Cao, Email: caoweiyu@hotmail.com.

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