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ORIGINAL ARTICLE
Year : 2022  |  Volume : 18  |  Issue : 2  |  Page : 567-575

Significance of vasohibin 1 in cancer patients: A systematic review and meta analysis


1 Department of Breast Disease Diagnosis and Treatment Center, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University; Department of Breast Disease Diagnosis and Treatment Center, Central Hospital Affiliated to Shandong First Medical University, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
2 Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, Shandong, China
3 Department of Breast Disease Diagnosis and Treatment Center, Central Hospital Affiliated to Shandong First Medical University, Jinan Central Hospital Affiliated to Shandong First Medical University; Department of Oncology, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
4 Department of Radiation Oncology; Department of Thoracic Surgery National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
5 Clinical Study Center, Shandong Cancer Hospital and Institute, Jinan, Shandong, China
6 Department of Breast Disease Diagnosis and Treatment Center, Central Hospital Affiliated to Shandong First Medical University, Jinan Central Hospital Affiliated to Shandong First Medical University; Medical Research and Laboratory Diagnostic Center, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China

Date of Submission19-Feb-2021
Date of Acceptance21-Sep-2021
Date of Web Publication27-Apr-2022

Correspondence Address:
Yunshan Wang
Medical Research and Laboratory Diagnostic Center, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250013, Shandong; Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong
China
Yuping Sun
Phase I Clinical Study Center, Shandong Cancer Hospital and Institute, Jinan 250117, Shandong
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.jcrt_281_21

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 > Abstract 


This study analyzed the role of vasohibin-1 (VASH1) in human cancer outcomes. Relevant original studies on VASH1 expression in cancers were searched from PubMed, ClinicalKey, and Cochrane Library databases. A meta-analysis was performed to evaluate the role of VASH1 in clinicopathological characteristics and overall survival (OS) of patients with tumors. Statistical analysis was performed using the RevMan v. 5.3 software. Our meta-analysis results showed that patients with high VASH1 expression experienced a significantly poor prognosis with a hazard ratio (HR) of 1.69 (95% confidence interval [CI], 1.16– 2.46, P = 0.006) for OS, and an HR of 2.21 (95% CI, 1.32–3.68, P = 0.003) for progression-free survival. Furthermore, the high expression of VASH1 was significantly relevant to advanced tumor node metastasis stages. Thus, VASH1 is a potential biomarker to predict unfavorable clinical outcomes, serving as a potential tumor treatment target.

Keywords: Clinicopathological characteristics, meta-analysis, overall survival, progression-free survival, vasohibion1


How to cite this article:
Liu S, Han B, Sun M, Wang J, Sun Y, Wang Y. Significance of vasohibin 1 in cancer patients: A systematic review and meta analysis. J Can Res Ther 2022;18:567-75

How to cite this URL:
Liu S, Han B, Sun M, Wang J, Sun Y, Wang Y. Significance of vasohibin 1 in cancer patients: A systematic review and meta analysis. J Can Res Ther [serial online] 2022 [cited 2022 Jul 7];18:567-75. Available from: https://www.cancerjournal.net/text.asp?2022/18/2/567/344239




 > Introduction Top


For decades, cancer has been the major cause of death in the global aging population. There were approximately 18.1 million new cancer cases and 9.6 million cancer deaths in 2018.[1] Tumor microenvironmental factors, such as tumor angiogenesis, are critical regulators that enable tumor growth, progression, and distant metastasis (DM). Therefore, a deeper understanding of the stimulatory and inhibitory molecules involved in the function of angiogenesis is crucial to develop future anticancer therapies.

Vasohibin-1 (VASH1) has been recently described as a novel negative feedback regulator of angiogenesis.[2],[3] Additionally, VASH1 inhibits tumor angiogenesis and prevents tumor growth and metastasis.[4] However, the prognostic significance of VASH1 in tumors remains controversial. There are reports that VASH1 is positively correlated with overall survival (OS), and other studies show otherwise.

This study explores the literature and conducts a meta-analysis on available data to summarize the feasible correlations between VASH1 expression and the prognosis and clinicopathological factors of patients with tumors.


 > Materials and Methods Top


This study was registered on PROSPERO (International Prospective Register of Systematic Reviews) with registration number CRD42020220623. This study followed the Systematic Reviews and Meta-Analyses (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement.[5]

Literature search strategy

We performed a systematic network reference search focusing on multiple databases: PubMed, ClinicalKey, and Cochrane Library, from inception to January 16, 2020, to obtain relevant studies published in English. The keywords searched were “Vasohibin-1,” “VASH1,” “KIAA1036,” “cancer,” “tumor,” “clinicopathology,” “prognosis,” and “survival.” Three authors independently selected the studies. The full text of any study that met the inclusion criteria was retrieved for further evaluation; else, they were excluded. Any disagreement between the two reviewers about data abstraction was resolved by discussion.

Inclusion and exclusion criteria

The selected criteria were (1) clinical cohort studies, written in English, evaluated VASH1 expression in samples from patients with tumor; (2) the expression level of VASH1 in patients with tumor was measured; (3) related clinicopathologic parameters were obtained; and (4) hazard ratio (HR) and 95% confidence interval (95% CI) for OS and progression-free survival (PFS) were provided directly or indirectly (survival curve provided) in the study. The exclusion criteria were (1) case reports; (2) studies that researched nonhuman models; and (3) duplicate publications.

Data extraction and quality evaluation

Two authors (Liu Shuai and Han Bing) extracted the data and information from all studies meeting the inclusion criteria, and the data and information were verified by another author (Sun Meili). Thus, the research was conducted independently. The data and information, including the name of the first author, year of publication, country name, cancer type, number of patients, number of patients in the high VASH1 expression group and the low VASH1 expression group, number of patients with large tumor size, tumor node metastasis (TNM) stage (III/IV) of the patients, the number of patients with lymph node metastasis (LNM), the number of patients with DM, and HR and 95% CI values for the survival outcomes in each group, were collected from every study.

Statistical analysis

The meta-analysis was performed using RevMan v. 5.3 software (RevMan Cochrane Collaboration; Oxford, England). The association between VASH1 expression and clinicopathological parameters was determined by pooled odds ratios (ORs) and 95% CI. OS and PFS were analyzed, and HRs and 95% CIs were directly derived from the studies. If only the Kaplan–Meier graphs were reported, then, the HR and 95% CI values were indirectly extracted using the method by Tierney et al.[6] The heterogeneity among the enrolled studies was assessed by the I2 metric and Q-statistics. Additionally, heterogeneity was evaluated using Q-test. P <0.05 for the Q-test and the I2 value >50% was proposed to be indexes of serious heterogeneity. The random- or fixed-effects model was applied for the studies depending on the heterogeneity test results. Sensitivity analysis was conducted to assess the steadiness of the outcomes. Publication bias was determined by a funnel plot.


 > Results Top


Eligible studies

Overall, studies were searched from different databases. As a result, 222 potentially relevant articles were identified through our initial search. After removing 78 duplicates, 144 articles were selected for further screening. After carefully screening the title, abstract, and full text, 13 studies were finally selected based on our inclusion and exclusion criteria and included in the final analysis [Figure 1]. Furthermore, we focused on the definition of the time-to-event date. OS is the duration from the date of diagnosis or treatment to death or last follow-up. PFS is the duration from diagnosis or treatment to the date of disease progression, the first recurrence, or both.
Figure 1: Flow chart of study selection

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Of the 13 studies, 7 were from China, and 6 were from Japan. Seven different tumors were included in this meta-analysis: one study on hepatocellular carcinoma, one on renal cell carcinoma, two on colorectal cancer, two on gastric cancer, two on ovarian carcinoma, three on lung cancer, and two on esophageal squamous cell carcinoma (ESCC) [Table 1]. The relationship between VASH1 expression and OS was reported in 13 studies. Four studies reported VASH1 expression and PFS; five described VASH1 expression and tumor size; seven focused on the relationship between VASH1 expression and LNM; five reported the relationship between VASH1 expression and DM; four discussed the relation of VASH1 expression and histological grade; four reported the association of VASH1 expression and TNM stage [Table 2]. VASH1 expression was assayed by different methods (immunohistochemistry, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction) in different studies. The patients with tumors in all 13 studies were divided into two groups (VASH1 high and VASH1 low expression groups).
Table 1: Characteristics of studies in the meta-analysis

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Table 2: The results of studies in the meta-analysis

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Meta-analysis

Association between vasohibin-1 expression and tumor size

To investigate the association between VASH1 expression and tumor size, the full text of 5 studies was evaluated, and 940 patients were included. Significant heterogeneity was observed in the studies (I2 = 82%, P = 0.0002); therefore, a random-effects model was employed for the analysis. The analysis displayed a pooled OR = 1.07 (95% CI: 0.52–2.20, P = 0.85) [Figure 2]. The expression of VASH1 was not markedly associated with tumor size. Because there was severe heterogeneity among the articles on tumor size, a sensitivity analysis was performed to analyze the impact of individual studies on the OR estimate by excluding a single study individually. The results showed that the study by DELIANG MA 2017 was responsible for the heterogeneity in meta-analysis. There was no proof of heterogeneity in the other studies (P = 0.97, I2 = 0%) after eliminating the DELIANG MA 2017 study. The pooled OR result was also changed to 1.57 (95% CI: 1.18–2.09, P = 0.002).
Figure 2: A forest plot describing the association between the vasohibin-1 expression and tumor size. There was no correlation between vasohibin-1 expression and tumor size

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Association between vasohibin-1 expression and lymph node metastasis

Next, we investigated the association between VASH1 expression and LNM in patients with cancer. In 7 articles, which included 1385 patients, those with LNM had different VASH1 expression levels. The random-effects model was conducted to determine the significant heterogeneity among the studies (I2 = 70%, P =0.003). The meta-analysis showed a pooled OR = 2.78 (95% CI: 1.72–4.48, P < 0.0001) [Figure 3]. LNM was increased in the high VASH1 expression group compared with LNM in the low expression group. Sensitivity analysis was performed, and relatively large heterogeneity was found among the studies on LNM. An article was deleted, and the other articles' heterogeneity was estimated to determine whether the results could have been significantly influenced by the deleted study. Sensitivity analysis results showed that the Lan Yu 2019 study was responsible for the heterogeneity in meta-analysis. There was no proof of heterogeneity in the other studies (P = 0.86, I2 = 0%) when the Lan Yu 2019 study was removed. The pooled OR result was significantly changed to 2.11 (95% CI: 1.65–2.69, P < 0.00001). Thus, LNM was related to high VASH1 expression.
Figure 3: A forest plot describing the association between the vasohibin-1 expression and lymph node metastasis. The lymph node metastasis was dramatically increased in the high vasohibin-1 expression group

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Association between vasohibin-1 expression and distant metastasis

Five articles, which consisted of 982 patients, reported that DM correlates with VASH1 expression levels. The random-effects model was conducted to determine the heterogeneity in the studies (I2 = 80%, P = 0.0004). The pooled ORs of the two groups were 3.43 (95% CI: 1.49–7.89, P = 0.004) [Figure 4]. Sensitivity analysis results showed that the Lan Yu 2019 study was responsible for the heterogeneity in meta-analysis. There was no proof of heterogeneity in the other studies after removing the Lan Yu 2019 study (P = 0.20, I2 = 36%). The pooled OR result was significantly changed to 2.33 (95% CI: 1.36–3.98, P = 0.002). The results showed that DM was associated with a high VASH1 expression.
Figure 4: A forest plot describing the association between the vasohibin-1 expression and distant metastasis. The high vasohibin-1 expression was significantly related to distant metastasis

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Association between vasohibin-1 expression and histological grade

Regarding different VASH1 expression levels, 4 studies comprising 652 patients included the number of patients with histological grades. The random-effects model was used, and there was significant heterogeneity in the studies (I2 = 87%, P < 0.0001). The analysis results showed a pooled OR = 1.94 (95% CI: 0.65–5.79, P = 0.24) [Figure 5]. The results showed no remarkable difference in the histological-grade incidence between the high VASH1 and the low VASH1 expression groups. These results showed that the expression of VASH1 did not correlate with histological grade. For heterogeneity across studies based on histological grade, sensitivity analysis was used. The sensitivity analysis results showed no heterogeneity in the meta-analysis after removing the Lan Yu 2019 study (P = 0.72, I2 = 0%). The pooled OR result was significantly changed to 1.08 (95% CI: 0.68–1.69, P = 0.75).
Figure 5: A forest plot describing the association between the vasohibin-1 expression and histological grade. There was no correlation between vasohibin-1 expression and histological grade

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Association between vasohibin-1 expression and tumor node metastasis stage

Four studies reported the TNM stage based on different VASH1 expression levels, and 536 patients were included. The fixed-effects model was employed because of no heterogeneity among the studies (I2 = 0%, P = 0.8). The analysis showed a pooled OR = 2.73 (95% CI: 1.89–3.94, P < 0.00001) [Figure 6]. The results showed that the advanced TNM stage was associated with high VASH1 expression.
Figure 6: A forest plot describing the association between the vasohibin-1 expression and tumor node metastasis stage. High vasohibin-1 expression was correlated with advanced tumor node metastasis stage

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Association between vasohibin-1 expression and progression-free survival

Four studies reported 443 patients with PFS and different levels of VASH1 expression. The random-effects model was conducted to determine the heterogeneity in those studies (I2 = 67%, P = 0.03). The analysis indicated a pooled HR = 2.21 [95% CI: 1.32–3.68, P = 0.003; [Figure 7]], showing a poor PFS in the high VASH1 expression group. A sensitivity analysis was also conducted in which one study was removed at a time, and the other studies were analyzed to confirm whether this could markedly influence the results. The sensitivity analysis results showed that the Tao Zhang 2014 study was the reason for the statistical heterogeneity. There was no heterogeneity in the meta-analysis after removing the Tao Zhang 2014 study (P = 0.73, I2 = 0%). The pooled OR result was significantly changed to 2.82 (95% CI: 1.93–4.12, P < 0.00001).
Figure 7: A forest plot describing the association between the vasohibin-1 expression and progression-free survival. High vasohibin-1 expression was negatively correlated with progression-free survival

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Association between vasohibin-1 expression and overall survival

Finally, 2325 patients in 13 studies were involved in analyzing the association between VASH1 expression and OS in cancer patients. The random-effects model was performed, and there was a large heterogeneity in the studies (I2 = 84%, P < 0.00001). The analysis revealed a pooled HR = 1.69 [95% CI: 1.16–2.46, P = 0.006; [Figure 8]], indicating poor survival in the high VASH1 expression group. Sensitivity analysis was employed for heterogeneity. None of the individual studies markedly altered the pooled OR when sequentially deleted, implying that our results were stable and robust.
Figure 8: A forest plot describing the association between the vasohibin-1 expression and overall survival. High vasohibin-1 expression was negatively associated with overall survival

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Publication bias

A funnel plot was employed to evaluate publication bias. The funnel plot revealed an evident asymmetry that indicated potential publication bias from the studies [Figure 9]. Publication bias implied the presence of a language bias, potential publication bias, a flawed methodologic design in smaller sample studies, or deficiency of publication with small samples or opposite results.
Figure 9: Publication bias of the literature

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 > Discussion Top


To the best of our knowledge, this study is the first meta-analysis to evaluate the association between VASH1 expression and clinicopathological characteristics, PFS, or OS of patients with cancer. Our major findings were that high VASH1 expression was positively correlated with LNM, DM, and TNM stages. Additionally, we demonstrated that high VASH1 expression was significantly associated with poor PFS and OS. However, there were no correlations between VASH1 expression and tumor size or histological grade.

Angiogenesis is the formation of new blood vessels from the existing vasculature,[7] and it plays an important role in various processes, including physiological and pathological conditions.[8] This process includes multiple sequential processes: the migration, growth, and differentiation of ECs. Additionally, angiogenesis is regulated by angiogenesis inhibitors and stimulators.[9] Angiogenesis stimulators promote the growth and survival of new blood vessels, and angiogenesis inhibitors interfere with blood vessel formation. Usually, there is a balance between angiogenesis inhibitors and stimulators, which regulate vascular homeostasis. However, angiogenesis occurs if the balance is broken for some reason, leading to angiogenic disorders.[9] Additionally, angiogenesis is important for the growth of tumors[10] because tumor cells need a sufficient supply of nutrients and oxygen and must transfer waste products. To date, antiangiogenic therapy as targeted therapy has been used by many patients. However, antiangiogenic treatments have not been proven to improve the long-term survival of patients.[11] Thus, there is an urgent need for greater understanding and successful manipulation of angiogenesis in cancer.

The VASH family contains two members: VASH1 and VASH2.[12] The members are expressed in different cells and control angiogenesis contradictorily. VASH1 expression in ECs inhibits angiogenesis, and VASH2 expression in mononuclear cells stimulates angiogenesis.[2] The human VASH1 gene has been detected on chromosome 14q24.3 and consists of seven exons.[13] There are two isoforms of human VASH1, namely, VASH1A and its splice variant, VASH1B.[14] The human VASH1A protein contains 365 amino acid residues, whereas the human VASH1B protein consists of 204 amino acid residues;[15] both have antiangiogenic activity.[16] VASH1 in ECs is usually induced by vascular endothelial growth factor-A (VEGF-A)/VEGF receptor 2 (VEGFR2) signaling.[3] Another factor, fibroblast growth factor 2 (FGF-2), can stimulate VASH1 expression.[3] Both inductions are mediated by protein kinase C-delta (PKCδ).[17] Immunohistochemical analysis showed that the VASH1 protein is present in ECs and tumor cells.[4],[18] VASH1 overexpression has been detected in various human malignancies[4],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29] and plays a multifunctional role that regulates various cellular functions, including cell proliferation, migration, and angiogenesis in ECs and cancer cells.[3] The relationship between VASH1 expression and OS is controversial. Some studies have demonstrated that VASH1 expression contributes to poor prognosis.[20],[21],[23],[24],[25],[27],[29],[30],[31] However, other studies could not confirm this conclusion; in studies of different cancer patients, the relationship between VASH1 expression and prognosis is positive.[22],[26],[32] Our meta-analysis is the first to investigate the correlation between VASH1 expression and OS. Our results show that VASH1 can serve as a notable biomarker indicating a poor prognosis for patients with cancer.

VASH1 has been detected in various cancer tissues and has been upregulated in several cancer types, playing an important role in angiogenesis and oncogenesis. It has been reported that VASH1 overexpression was found in breast, colon, lung, liver, and other cancers. VASH1 has complex effects on various cancers through different mechanisms. Watanabe et al. reported that VASH1 is selectively expressed in ECs and induced by VEGF and basic FGF.[3] VASH1 can influence VEGF expression by feedback regulation.[3] Shimizu et al. reported that VEGF induced VASH1 expression by the VEGFR2-PKC signal pathway.[17] Takahiro Heishi et al. demonstrated that exogenous VASH1 has broad-spectrum anti-lymphangiogenic activity and can prevent tumor lymphangiogenesis and regional LNM in animal models.[33] Exogenous VASH1 (an angiogenesis and lymphangiogenesis inhibitor) prevents tumor progression, angiogenesis, and lymphangiogenesis.[4],[33] However, endogenous VASH1 is highly expressed in tumor tissues and hardly plays a role in tumor progression, angiogenesis, and lymphangiogenesis. Recent studies have indicated that several factors regulate endogenous VASH1. MicroRNAs (miRNAs) and long noncoding RNAs (lncRNAs) participate in the progression of different cancers.[34] Cancer-associated miRNAs play a critical role in tumor biology.[35] In brain metastasis tissues, miR-143-3p is upregulated, promoting lung cancer's angiogenesis by silencing VASH1.[36] In cervical squamous cell carcinoma, the miR-221-3p-VASH1 axis triggers the extracellular signal-regulated kinase/protein kinase B signaling pathway and promotes lymphangiogenesis and lymphatic metastasis.[37] In breast cancer, miR-4530 inhibits VASH1 expression, promotes angiogenesis, supports cancer cell proliferation, and suppresses apoptosis.[38] lncRNA RBMS3-AS3 is poorly expressed in prostate cancer (PCa). RBMS3-AS3 targets miR-4534 and prevents PCa progression by promoting VASH1 expression, highlighting a theoretical target for PCa treatment.[39] In ovarian cancer tissue, enhancer of zeste homolog 2 is stimulated by VEGF stimulation, which methylates and silences VASH1, promoting angiogenesis.[40] VASH1 mutations have been observed in different cancers.[41] The precise mechanism of VASH1 is not entirely understood, needing further investigations of the mechanism and regulatory pathways of VASH1.

Because VASH1 is an angiogenesis inhibitor, VASH1 overexpression in tumor tissues should relate to a better prognosis. Several recent studies have suggested that VASH1 could be an independent favorable prognostic marker in various cancer types.[19] Patients with renal cell carcinoma,[22] ESCC,[26] and non-small cell lung cancer (NSCLC)[32] in the high VASH1 expression group had significantly good PFS and OS. However, patients with hepatocellular carcinoma,[21] upper tract urothelial carcinoma,[20] PCa,[23] colorectal cancer,[18],[24] NSCLC,[25] gastric cancer,[30] ovarian carcinoma,[28],[31] renal cell carcinoma,[27] and ESCC[29] in the high VASH1 expression group had significantly poor survival. This study retrospectively analyzed the correlations of VASH1 expression levels with the cancer clinicopathological factors of different patients with cancer. Our study showed that high VASH1 expression was remarkably positively associated with LNM, DM, and TNM stage and was not associated with tumor size or histological grade. The meta-analysis showed that VASH1 expression was significantly negatively correlated with PFS and OS. Altogether, these results indicate that VASH1 plays a critical role through different pathways in regulating different tumors. Therapeutic strategies targeting VASH1 are promising for patients with cancer treatment. Future studies should identify the mechanism regulating VASH1 expression in the tumor and peri-tumor microenvironment to further understand its role in cancer prognosis.

There was significant heterogeneity among VASH1 expression, clinicopathological characteristics, and OS. Several reasons might have caused the heterogeneity. First, the different histogenesis and cutoff points of high VASH1 expression may have influenced our results. Furthermore, the sample sizes and the number of studies involved in the analysis may have caused the heterogeneity. Second, although most survival data were directly collected from research, the HR values were extracted from survival curves in some studies, which are less reliable than direct data from actual statistical data and may lead to possible deviations. Third, the studies in this meta-analysis were limited to studies published in English, which may have led to publication bias. Fourth, the patients in this study were only from Asia, and thus, this study lacked racial diversity, which may result in population bias.

We attempted to provide a comprehensive analysis; however, there were several limitations to our study. First, there were different approaches for evaluating VASH1 expression levels, different antibodies, and different cancer specimens from different regions in different studies. There was no standardized assay to measure VASH1 expression. Second, studies published in other languages were excluded, and negative results in some studies may not have been reported, leading to publication bias. Despite these limitations, our study proves the correlation between VASH1 expression and clinicopathological characteristics and OS. The results of our studies may improve anticancer therapy by understanding the role of VASH1 in different cancers.

Conclusively, this meta-analysis indicates that the high expression of VASH1 is significantly relevant to advanced LNM, DM, TNM stage, poor PFS, and OS. VASH1 can serve as a potential biomarker to predict unfavorable survival in patients with cancer and may have potential value in being used in molecularly targeted treatments. The high expression of VASH1 is unassociated with tumor size and histological grade. Long-term, longitudinal, and high-quality studies are necessary to further explore the effect and relevant mechanisms of VASH1 in cancer.

Financial support and sponsorship

This work was supported by the Shandong Medical and Health Science and Technology Development Project (grant no. 2016WS0136), Jinan Medical and Health Science and Technology Development Project (grant no. 2020-4-24), the Youth Fund from Natural Science Foundation of Shandong Province (grant no. ZR2020QH252), Scientific and Technical Innovation Plan in clinical medicine of Jinan (grant no.202019005) and Natural Science Foundation of Shandong Province (grant no. ZR2019MH042).

Conflicts of interest

There are no conflicts of interest.



 
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