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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 5  |  Page : 1157-1164

Prognostic value and functional bioinformatic analysis of spindle- and kinetochore-associated protein 1 in stage IIA esophageal squamous cell carcinoma


1 Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
2 Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China

Date of Submission10-Jul-2020
Date of Decision18-Jul-2020
Date of Acceptance05-Aug-2020
Date of Web Publication29-Sep-2020

Correspondence Address:
Zhongmin Peng
Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jing 5 Road, Jinan, Shandong 250021
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_953_20

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 > Abstract 


Background: As one of the most common malignant tumors of the digestive tract, esophageal squamous cell carcinoma (ESCC) is an advanced metastatic cancer with an extremely high mortality rate and the highest prevalence rate in China. Spindle- and kinetochore-associated protein 1 (SKA1), an essential member involved in chromosome separation during mitosis, has been indicated as a potential biomarker in the pathogenesis and development of various types of malignant tumors; however, the exact functions of SKA1 in ESCC are still unclear.
Patients and Methods: SKA1 expression was explored in stage IIA ESCC and corresponding healthy esophageal mucosa tissues through immunohistochemistry and reverse transcription–quantitative polymerase chain reaction and was further validated using The Cancer Genome Atlas (TCGA) database of the online tool UALCAN. Then, the clinicopathological correlations of SKA1 were analyzed based on the follow-up data. Furthermore, using the online tool LinkedOmics, the correlation test, gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of SKA1 were analyzed using high-throughput sequencing data of ESCC patients from TCGA dataset.
Results: The expression level of SKA1 was markedly upregulated in ESCC tissues. Upregulation of SKA1 significantly correlated with higher pathological T stage (P = 0.003) and poorer overall survival (P = 0.013). GO and pathway enrichment analyses of SKA1 in ESCC revealed that SKA1 was involved in a number of classical cell cycle-related pathways that contribute to special biological processes in tumorigenesis and development of ESCC.
Conclusion: The results of this study demonstrate that SKA1 may act as a prognostic biomarker for stage IIA ESCC. Combined with the bioinformatic analysis, SKA1 could potentially serve as a therapeutic target for ESCC.
Conclusion: The results coming from the present study demonstrated that SKA1 may act as a prognostic biomarker for stage IIA ESCC. Combined with the bioinformatic analysis, SKA1 could serve as a potential therapeutic target for ESCC.

Keywords: Esophageal squamous cell carcinoma, prognosis, recurrence, UALCAN


How to cite this article:
Hu D, Zhang M, Peng Z. Prognostic value and functional bioinformatic analysis of spindle- and kinetochore-associated protein 1 in stage IIA esophageal squamous cell carcinoma. J Can Res Ther 2020;16:1157-64

How to cite this URL:
Hu D, Zhang M, Peng Z. Prognostic value and functional bioinformatic analysis of spindle- and kinetochore-associated protein 1 in stage IIA esophageal squamous cell carcinoma. J Can Res Ther [serial online] 2020 [cited 2020 Oct 26];16:1157-64. Available from: https://www.cancerjournal.net/text.asp?2020/16/5/1157/296454




 > Introduction Top


Esophageal cancer (EC) is a common digestive tract malignant tumor and the sixth most common cause of cancer-related death globally in 2018.[1],[2] In 2015, EC was the fourth most common cause of cancer-related mortality in China.[3] Esophageal squamous cell carcinoma (ESCC) is the predominant histological type of EC and has the highest incidence in China.[4],[5] Smoking tobacco, drinking alcohol, a diet lacking fruits and vegetables, gastroesophageal reflux, and certain susceptibility-related genes are involved in the etiology of ESCC.[6] Despite significant improvements in therapeutic modalities, including radiotherapy, chemotherapy, and surgery,[7] the prognosis of ESCC remains very poor, and the 5-year overall survival (OS) rate was only 20.9% in China in 2015.[8],[9] Even for stage IIA ESCC with complete resection, the 5-year survival rate is merely 30%–50%.[10] The most common reason for poor prognosis is lymphatic metastatic recurrence (LMR).[11] Therefore, it is imperative to investigate reliable biomarkers to help predict the LMR risk for ESCC patients as a guide for additional adjuvant treatment.

Spindle- and kinetochore-associated protein 1 (SKA1), a member of the family of spindle- and centromere-binding proteins, is a microtubule-binding protein.[12],[13] The SKA complex is essential for the stabilization of the kinetochore-spindle microtubule attachment during mitosis. The depletion of SKA1 may cause severe defects in chromosome segregation.[14] Prior studies have demonstrated that aberrantly upregulated expression of SKA1 is affiliated to poor prognosis in several kinds of cancers.[15] Nevertheless, no study has reported the correlation between SKA1 expression and LMR. Moreover, the prognostic value of SKA1 and its biological roles in ESCC is still not understood.

In our study, we aimed to explore the relationships between SKA1 expression and clinicopathological parameters, as well as the 3-year LMR and OS rates with stage IIA ESCC patients. In addition, we investigated the function of SKA1 in ESCC by bioinformatic analysis using publicly available data.


 > Materials and Methods Top


Ethics and consent

This study was approved by the Research Ethics Committee of Shandong Provincial Hospital affiliated to Shandong First Medical University (Jinan, China) as we reported in the previous article.[16] The research methodologies were carried out according to the standards expressed in the Declaration of Helsinki. The informed consent was obtained from all participants in our hospital, and the form of the datasets retrieved from published literature ensured that written informed consent was retrieved from those participants.

Patients and tissues

Forty pairs of ESCC tissues and the matching corresponding healthy esophageal mucosa (CHEM, at least 5 cm away from the margin of the tumor) were collected and stored in liquid nitrogen from June 2018 to September 2018. In addition, another 113 pairs of paraffin-embedded ESCC and CHEM specimens were obtained from patients between March 2015 and December 2015. Light microscopy was requisitioned to ensure the absence of necrosis, deterioration, or tumor in the CHEM tissue samples. In total, there were 31 females and 82 males enrolled in our study, with a median age of 62 years (range of 33–75 years). The clinicopathological information is listed in [Table 1]. The inclusion criteria included the following: (i) complete tumor resection (R0) achieved through Ivor Lewis esophagogastrostomy with thoracoabdominal two-field lymphadenectomy;[8] (ii) as per criteria of the Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) staging system,[17] only pathological stage IIA (pT2-3N0M0) ESCC patients were recruited; (iii) a lack of residual cancer cells under the upper, lower, and lateral edges confirmed by pathological examination; (iv) more than 12 lymph nodes were dissected; (v) no preoperative neoadjuvant chemotherapy or postoperative adjuvant treatment; (vi) no history of previous malignancies; (vii) no severe postoperative complications; and (VIII) records of no less than a complete 3-year follow-up review and the first LMR site.
Table 1: Spindle- and kinetochore-associated protein 1 expression in patients with stage IIA esophageal squamous cell carcinoma and correlation with clinicopathological variables, survival, and recurrence

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Immunohistochemistry analysis and immunohistochemical score

The streptavidin-peroxidase immunohistochemical method was used to examine the expression of the SKA1 protein, which was conducted as described previously.[18] Rabbit anti-SKA1 primary antibody (cat. no. ab91550; Abcam) and biotin goat anti-rabbit IgG H&L secondary antibody (cat. no. ab6720; Abcam) were used at a dilution of 1:50 and 1:2,000, respectively. The standard for immunohistochemical score (IHS) evaluation was mentioned in our previous study.[18] Each case with an IHS ≥4 was considered to have high expression. Blinded to the patients' clinical data, two experienced pathologists scored all the samples independently. The final score was agreed on a result by re-analysis and discussion.

Reverse transcription–quantitative polymerase chain reaction

Total RNA was extracted using TRIzol ® (Invitrogen; Thermo Fisher Scientific, Inc.) according to the manufacturer's protocol.[16] Superscript III reverse transcriptase (Invitrogen; Thermo Fisher Scientific, Inc.), was utilized to prepare complementary DNA (cDNA) according to the manufacturer's protocol. Then, quantitative polymerase chain reaction (qPCR) with SYBR Green qPCR SuperMix (Invitrogen; Thermo Fisher Scientific, Inc.) was used to detect mRNA expression with the following conditions: 95°C for 2 min, 40 cycles of 95°C for 15 s, and 60°C for 45 s. GAPDH cDNA was used as an internal standard. The following primer pairs were used: SKA1 forward, 5'TTC CCA TTT GCC TCA AGT AAC AG3' and reverse, 5'GGA ACA CCA TTG AAC TCA TCA CAA G3'; and GAPDH forward, 5'GCA CCG TCA AGG CTG AGA AC3' and reverse, 5'TGG TGA AGA CGC CAG TGG A3'. The 2ΔΔCq method was used to calculate elative expression.[19]

Follow-up after surgery

Patients were examined regularly every 3–6months after discharge, including thorough physical examination, chest and upper abdomen contrast-enhanced CT scan, ultrasonography of the abdomen, positron emission tomography (PET), bone scintigraphy, and cerebral CT.[20] According to specific imaging or physical examinations, fine-needle aspiration biopsies were used to determine whether recurrence occurred or not. All follow-ups ended in December 2018, and the maximum follow-up period was 36 months.

Statistical analysis

SPSS 21.0 software (SPSS, Inc., IBM Corp., Armonk, NY, USA) was used for all statistical analyses. Significant differences between SKA1 expression and clinicopathological parameters were assessed using the Chi-square test. Survival curves and recurrence curves were calculated by the Kaplan–Meier method using a log-rank test. Cox regression multivariate analysis was performed to determine independent prognostic factors. A statistically significant difference was confirmed when P < 0.05.

UALCAN

The new web resource UALCAN (http://ualcan.path.uab.edu),[21] which includes level 3 RNA-seq and clinical data of 31 cancer types from The Cancer Genome  Atlas More Details (TCGA) database, allows researchers and doctors to explore the relative expression of target genes of interest by comparing the transcriptional expression of tumors and healthy samples with comparative clinicopathological parameters. In our study, UALCAN was used to analyze the expression of SKA1 mRNA in ESCC and healthy esophageal tissues and its association with clinicopathological parameters. Student's t-test was used to compare the differences in transcriptional expression levels, and the statistically significant difference was confirmed when P < 0.01.

The Cancer Genome Atlas and LinkedOmics

TCGA provides both large-scale genome sequencing and pathological data to help TCGA users to analyze more than 30 different kinds of malignant tumors.[20] The publicly available portal LinkedOmics (http://www.linkedomics.org/login.php) includes multiomics data from cancer types found in TCGA.[17]

In our study, the esophageal carcinoma mRNA sequencing dataset (HiSeq RNA 01/28/2016) named TCGA-ESCA was used for further analyses of SKA1 through the online tool LinkedOmics. The total number of patients enrolled in TCGA-ESCA was 185, and 96 of them were ESCC patients. The high-throughput sequencing data from ESCC patients were collected for analysis. The correlation analysis of SKA1 was performed according to the Pearson correlation coefficient. The top 50 positively and negatively correlated genes were screened and depicted in a heat map. Gene ontology (GO) enrichment analyses, such as biological processes (BPs), cell components (CCs), and molecular functions (MFs), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were conducted using the Gene Set Enrichment Analysis (GSEA) of the online tool LinkedOmics. The ggplot2 and Hmisc packages in R software (http://www.r-project.org/) were used for visualization.[22]


 > Results Top


SKA1 mRNA and protein expression levels are significantly upregulated in ESCC tissues.

SKA1 mRNA expression level was determined using real-time qPCR in ESCC tissues and matched CHEM tissues. Meanwhile, SKA1 protein expression levels were detected through immunohistochemistry (IHC) with matched samples. Compared to CHEM tissues, expression levels of SKA1 mRNA in ESCC tissues were remarkably higher [Figure 1]c. In addition, SKA1 was mainly located in the protoplasm of cancer cells, as shown in [Figure 1]a. SKA1 protein expression was markedly increased in ESCC tissues compared to CHEM tissues [Figure 1]a and [Figure 1]b. In the 113 samples, high SKA1 expression levels were detected in 64 (56.6%) ESCC samples and only 22 (19.5%) CHEM samples.
Figure 1: SKA1 upregulation in ESCC tissues is significant. (a) Immunohistochemistry staining of SKA1 expression in ESCC tissues (n = 113) (×400). (b) Immunohistochemistry staining of SKA1 expression in CHEM tissues (n = 113) (×400). (c) Levels of SKA1 mRNA expression in ESCC tissues (n = 40) and CHEM tissues (n = 40) measured by reverse transcription–quantitative polymerase chain reaction. (d) Increased SKA1 mRNA expression in ESCC tissues compared to healthy tissues in The Cancer Genome Atlas, performed using the online tool UALCAN. **P < 0.01; ***P < 0.001. ESCC: Esophageal squamous cell carcinoma; CHEM: Corresponding healthy esophageal mucosa; SKA1: Spindle- and kinetochore-associated protein 1

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To validate these results, the TCGA database was used to search for SKA1 mRNA expression levels in ESCC. SKA1 mRNA expression levels in cancer tissues were obviously upregulated compared with normal tissues [Figure 1]d.

The relationship between spindle- and kinetochore-associated protein 1 expression and clinicopathological parameters by immunohistochemistry analysis

According to the inclusion criteria previously described, 113 ESCC patients were enrolled in the study. The relationship between SKA1 expression and clinicopathological features is shown in [Table 1]. χ2 analysis revealed no significant associations between the level of SKA1 expression and age, gender, tumor size, or differentiation degree. Conversely, the upregulation of SKA1 was remarkably correlated with pathological T stage [Table 1].

The upregulation of SKA1 predicts a poorer clinical prognosis and a higher risk of LMR in stage IIA ESCC patients.

According to complete follow-up data, the 3-year OS and LMR rates of stage IIA ESCC patients with upregulated expression levels of SKA1 were 62.5% and 51.6%, respectively. Meanwhile, the 3-year OS and LMR rates of patients with low expression levels of SKA1 were 83.7% and 30.6%, respectively. These results exhibited a significant difference between patients with various expression levels of SKA1 [Table 1].

The results of the Kaplan–Meier analysis indicated that the 3-year OS rate was clearly decreased in patients with upregulated SKA1 levels [P = 0.013; [Figure 2]a. On the contrary, the LMR rate was significantly increased in this group [P = 0.016; [Figure 2]b. Therefore, ESCC patients with upregulation SKA1 might suffer a worse prognosis. The multivariate Cox regression analysis suggested that pathological T stage and upregulation of SKA1 protein were independent predictive factors for stage IIA ESCC patients [Table 2].
Figure 2: (a) Kaplan-Meier analysis of overall survival in stage IIA ESCC patients according to SKA1 expression level. (b) Kaplan-Meier analysis of lymphatic metastatic recurrence in stage IIA ESCC patients according to SKA1 expression level. SKA1: Spindle- and kinetochore-associated protein 1; ESCC: Esophageal squamous cell carcinoma

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Table 2: Cox multivariate regression analysis of prognostic factors in stage IIA esophageal squamous cell carcinoma patients

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Correlation analysis of spindle- and kinetochore-associated protein 1 in esophageal squamous cell carcinoma

SKA1 correlation was calculated via the LinkedOmics online tool for ESCC. The Pearson correlation test was used to identify the genes correlated with SKA1 in ESCC. The result showed that there were 20,104 genes associated with SKA1. The 50 top positively and negatively correlated genes were screened and used to create the heat map [Figure 3].
Figure 3: Correlation analysis of SKA1 in ESCC patients. (a) Fifty top positively related genes; (b) 50 top negatively related genes; (c) Pearson correlation test of SKA1 and related genes. SKA1: Spindle- and kinetochore-associated protein 1; ESCC: Esophageal squamous cell carcinoma

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Gene ontology and pathway enrichment analysis of spindle- and kinetochore-associated protein 1 and its co-expressed genes in esophageal squamous cell carcinoma

The GO and KEGG analyses were utilized to explore the functional enrichment of SKA1 and its correlated genes [Figure 4].
Figure 4: Gene ontology analysis, including biological processes, cellular components, and molecular functions, and Kyoto Encyclopedia of Genes and Genomes enrichment analysis of SKA1 in ESCC. SKA1: Spindle- and kinetochore-associated protein 1; ESCC: Esophageal squamous cell carcinoma

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BPs, CCs, and MFs were included in GO analysis. The results exhibited that the BPs, such as GO: 0006260(DNA replication), GO: 0007062 (sister chromatid cohesion), GO: 0051301 (cell division), GO: 0007067 (mitotic nuclear division), GO: 0000082 (G1/S transition of mitotic cell cycle), GO: 0000086 (G2/M transition of mitotic cell cycle), GO: 0000070 (mitotic sister chromatid segregation), GO: 0007059 (chromosome segregation), GO: 0006270 (DNA replication initiation), and GO: 0007049 (cell cycle), were markedly controlled by SKA1 and its correlated genes in ESCC. SKA1 and its correlated genes also significantly regulated CCs, such as GO: 0005654 (nucleoplasm), GO: 0000777 (condensed chromosome kinetochore), GO: 0000776 (kinetochore), GO: 0000790 (nuclear chromatin), GO: 0005876 (spindle microtubule), GO: 0005874 (microtubule), and GO: 0005819 (spindle). Last but not least, some MFs were also significantly affected by the correlated genes, such as GO: 0005515 (protein binding), GO: 0003682 (chromatin binding), GO: 0003697 (single-stranded DNA biding), GO: 0003690 (double-stranded DNA binding), and GO: 0008017 (microtubule binding). Observably, all the correlated genes are closely related to the regulation of cell cycle.

In addition, KEGG analysis was exploited to define the functional pathways associated with SKA1 and its correlated genes. Fourteen pathways showed the most relevant association with these genes. As shown in [Figure 4], hsa03030: DNA replication, hsa04110: cell cycle, hsa03410: base excision repair, hsa03430: mismatch repair, hsa04114: oocyte meiosis, and hsa03420: nucleotide excision repair were involved in the carcinogenesis, tumorigenesis, and development of ESCC.

To gain further insight on ESCC pathogenesis, GSEA based on the TCGA database was performed. The results demonstrated that activated gene sets correlated with the cell cycle checkpoint signaling pathway normalized enrichment score [NES 2.54; [Figure 5]a, DNA replication signaling pathway [NES 2.72; [Figure 5]b, DNA recombination signaling pathway [NES 2.56; [Figure 5]c, spindle organization signaling pathway [NES 2.47; [Figure 5]d, negative regulation of cell cycle process signaling pathway [NES 2.40; [Figure 5]e, and chromosome segregation signaling pathway [NES 2.78, [Figure 5]f. These pathways were more associated with patients with a higher SKA1 expression level compared to those with lower expression levels. All pathways had P < 0.01 and false discovery rate = 0.
Figure 5: SKA1 regulation of certain tumor-related pathways. Enrichment plots are displayed for activated gene sets related to (a) cell cycle checkpoint, (b) DNA replication, (c) DNA recombination, (d) spindle organization, (e) negative regulation of cell cycle process, and (f) chromosome segregation signaling pathways. SKA1: Spindle- and kinetochore-associated protein 1; NES: Normalized enrichment score; FDR: False discovery rate

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 > Discussion Top


ESCC is one of the most lethal types of malignant tumors in the world.[2],[23] The incidence rate of ESCC is particularly high in China.[5] Regardless of the improved early diagnosis and combined therapy, the prognosis of ESCC remains unsatisfactory. Based on the National Comprehensive Cancer Network guidelines for ESCC, pathological stage IIA ESCC patients need not to accept adjuvant therapy. However, a shocking fact is the 5-year OS rate that is merely 30%–50%, even for stage IIA ESCC patients.[10] Previous studies have confirmed that the majority of the patients will experience postoperative LMR, which is the main cause of treatment failure and eventually death.[7],[11] Despite the tumor-node-metastasis (TNM) staging system, which lacks accuracy and sensitivity, the underlying molecular mechanism of ESCC tumorigenesis and development is crucial and can be further understood by identifying and evaluating ESCC-associated oncogenes and the associated molecular and biological functions.

SKA1, located on chromosome 18q21.1, is indispensable for maintaining the stability of the kinetochore and microtubules. SKA1 participates in SKA complex formation, which promotes correct transitioning through the whole process of mitosis.[13] Emerging evidence has revealed the involvement of SKA1 in the carcinogenesis and development of a variety of malignant tumors.

Upregulation of SKA1 has been shown in various malignant tumors, including non-small cell lung cancer, papillary thyroid carcinoma, gastric cancer, papillary thyroid carcinoma, and oral adenosquamous carcinoma.[15] Zhao et al. reported that SKA1 overexpression positively correlates with perineural invasion, higher recurrence rates, and lower survival rates in patients with primary salivary adenoid cystic carcinoma.[15] Chen et al. demonstrated that expression of SKA1 is upregulated in hepatocellular carcinoma and thus could function as a prognostic biomarker. Furthermore, Tian et al. discovered that the high expression of SKA1 may be closely associated with early recurrence in bladder cancer.[24]

As for molecular and biological functions, previous studies have identified SKA1 as an oncogene that may promote carcinogenesis by regulating proliferation, apoptosis, invasion, and migration in cancer cells. Upregulated expression of SKA1 could promote cell proliferation by affecting the cell cycle progress in several types of cancer, including gastric cancer,[25] bladder cancer,[24] and prostate cancer.[26] Knocking down SKA1 expression could interfere with cell proliferation, induce cell cycle arrest, promote apoptosis, and reduce migration in bladder cancer,[24] non-small cell lung cancer,[27] hepatocellular carcinoma, adenoid cystic carcinoma,[28] and prostate cancer.[26]

IHC performed during this study showed that the expression of SKA1 was upregulated in 56.6% of ESCC specimens compared with matched CHEM specimens. In addition, compared to CHEM tissues, ESCC tissues had significantly higher SKA1 mRNA expression levels, which were further confirmed by analysis of TCGA dataset. Consistent with previous studies, we identified that upregulation of SKA1 is associated with a higher probability of LMR and a poor clinical prognosis; therefore, SKA1 could there serve as an independent prognostic factor in stage IIA ESCC. Consequently, these results suggest that reactivation of SKA1 may be a vital factor promoting ESCC development.

In addition, HiSeq RNA data for ESCC from TCGA were used to learn the function of SKA1. The correlation test and GO and KEGG enrichment analyses were carried out based on the HiSeq data. The results of correlation test showed that cell cycle-related genes, including CCNE2, CDC6, CDK1, CDK2, CDK4, CDKN2A, and RBL1, were closely related to SKA1. Further, GO and KEGG pathway enrichment analyses revealed that SKA1 and its correlated genes are closely related to ESCC cell cycle progression. Moreover, the pathways resulting from the GSEA, including the chromosome segregation signaling pathway, DNA replication signaling pathway, negative regulation of cell cycle process signaling pathway, spindle organization signaling pathway, cell cycle checkpoint signaling pathway, and DNA recombination signaling pathway, are all classical cell cycle-related pathways that contribute to cell proliferation, apoptosis, migration, and invasion. These findings indicate that SKA1, a member of the SKA complex, may be a key factor in ESCC tumorigenesis and development by regulating cell cycle progression.

To the best of our knowledge, few studies have investigated the role of SKA1 in ESCC. The results from our study indicate that SKA1 could serve as a potential ESCC therapeutic target. However, certain limitations exist in our study. First, in vitro and in vivo experiments need to be performed to further explore the biological function of SKA1 in ESCC. Furthermore, the underlying molecular mechanism of SKA1 promoting the pathogenesis and development of ESCC was not investigated. Therefore, further studies are required with the aim of overcoming these problems.


 > Conclusion Top


This study identified the upregulation and potential prognostic value of SKA1 in stage IIA ESCC. The bioinformatic analysis of the biological function of SKA1 suggested that it may be a key factor in ESCC tumorigenesis and development. Taken together, our findings indicate that SKA1 is a valuable prognostic biomarker for stage IIA ESCC and, furthermore, a potential therapeutic target for treating ESCC.

Financial support and sponsorship

The present study was supported by the Nature Science Foundation of Shandong Province (grant no. ZR2019PH034).

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

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