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Aberrant expression of vasculogenic mimicry, PRRX1, and CIP2A in clear cell renal cell carcinoma and its clinicopathological significance

Wang, Xiaolin MDa,b; Yang, Ruixue MDa,b; Wang, Qi MDa,b; Wang, Yichao MDa,b; Ci, Hongfei MDa,b; Wu, Shiwu MDa,b,*

Section Editor(s): Ding., Jianxun

doi: 10.1097/MD.0000000000017028
Research Article: Observational Study

Vasculogenic mimicry (VM) involves a tubular structure with a basement membrane that is similar to and communicates with vessels but functions independent of blood vessels to nourish tumor cells, promote tumor progression, invasion, and metastasis, with reduced 5-year survival rates. Tumor cell proliferation, invasion, and metastasis are promoted by the epithelial-mesenchymal transition (EMT). Paired-related homeobox 1 (PRRX1), a newly discovered EMT inducer, has been shown to correlate with metastasis and prognosis in diverse cancer types. Cancerous inhibitor of protein phosphatase 2A (CIP2A) was initially recognized as an oncoprotein. In this study, we aimed to investigate the expression and clinical significance of the EMT markers PRRX1, CIP2A and VM in clear cell renal cell carcinoma (CCRCC) and their respective associations with clinicopathological parameters and survival.

Expression of PRRX1, CIP2A and VM in whole CCRCC tissues from 110 patients was analyzed by immunohistochemical and histochemical staining. Fisher's exact test or the chi square test was used to assess associations with positive or negative staining of these markers and clinicopathological characteristics.

Positive expression of CIP2A and VM presence was significantly higher and that of PRRX1 was significantly lower in CCRCC tissues than in corresponding normal tissues. Furthermore, positive expression of CIP2A and VM was significantly associated with tumor grade, size, lymph node metastasis (LNM) stage, and tumor node metastasis (TNM) stage and inversely associated with overall survival time (OST). Moreover, levels of PRRX1 were negatively associated with tumor grade, size, LNM stage, and TNM stage. The PRRX1 subgroup had a significantly longer OST time than did the PRRX1 subgroup. In multivariate analysis, high VM and CIP2A, tumor grade, LNM stage, TNM stage, and low PRRX1 levels were identified as potential independent prognostic factors for OST in CCRCC patients.

VM and expression of CIP2A and PRRX1 represent promising biomarkers for metastasis and prognosis and potential therapeutic targets in CCRCC.

aDepartment of Pathology, The First Affiliated Hospital of Bengbu Medical College

bDepartment of Pathology, Bengbu Medical College, Bengbu, Anhui Province, China.

Correspondence: Shiwu Wu, Department of Pathology, The First Affiliated Hospital of Bengbu Medical College, Bengbu Medical College, No.287, Changhuai Road, Bengbu 233003, Anhui Province, China (e-mail:

Abbreviations: AJCC = American Joint Committee on Cancer, CCRCC = clear cell renal cell carcinoma, CIP2A = cancerous inhibitor of protein phosphatase 2A, CSC = cancer stem cell, DM = distant metastasis, ECM = extracellular matrix, EMT = epithelial-mesenchymal transition, HPF = high-power field, LNM = lymph node metastasis, OST = overall survival time, PAS = periodic acid-Schiff, PBS = phosphate-buffered saline, PP2A = protein phosphatase 2A, PRRX1 = paired-related homeobox 1, TNM = tumor-node-metastasis, VM = vasculogenic mimicry, WHO = World Health Organization.

How to cite this article: Wang X, Yang R, Wang Q, Wang Y, Ci H, Wu S. Aberrant expression of vasculogenic mimicry, PRRX1, and CIP2A in clear cell renal cell carcinoma and its clinicopathological significance. Medicine 2019;98:36(e17028).

All clinical samples were solicited and obtained after receiving written consent from the patient, and the study was approved by the Ethical Committee of Bengbu Medical College and performed in accordance with the ethical guidelines of the Declaration of Helsinki (No. BBMUEC201718).

This study was supported by the Nature Science Foundation of Anhui Province (No. 1708085MH230), the Nature Science Key Program of Bengbu Medical College (No. BYKY1711ZD), the Key Projects of Support Program for Outstanding Young Talents in Colleges and Universities of Anhui Province (No. gxyqZD2016160) and the Nature Science Key.

The authors declare that they have no competing interests in this work.

The authors have no conflicts of interest to disclose.

Received May 20, 2019

Received in revised form July 30, 2019

Accepted August 12, 2019

This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

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1 Introduction

Kidney cancer is classified as the 16th most common cause of death from cancer worldwide,[1] and the majority of kidney cancers (70%) are classified as clear cell renal cell carcinoma (CCRCC).[2] Despite nephrectomy with curative intent, ∼30% of CCRCC patients with localized disease eventually develop metastasis; therefore, identification of new early diagnostic tools and therapeutic methods for CCRCC is urgently needed.

Some researchers have found that when endothelium-dependent angiogenesis is not sufficient to support the rapid growth of tumor tissue, tumor cells themselves form a vessel-like, tubular structure with a basement membrane that communicates with blood vessels and acts as an angiogenesis-independent component of the tumor's microcirculation or microenvironment, a process known as vasculogenic mimicry (VM).[3,4] VM involves a lumen-like structure that provides nutrients and blood and promotes metastasis.[5] There are three main structures in VM: stem cell-like tumor cells, the extracellular matrix (ECM), and lumen-like structures connected to the circulatory system.[6] VM has been observed in a variety of malignant tumors, such as breast cancer, prostate cancer, liver cancer, nonsmall cell lung, and malignant glioma. Furthermore, many studies have shown that patients with cancer-related VM are prone to metastasis and have a poor prognosis.[5–8,27]

The epithelial mesenchymal transition (EMT) is a process in which cells lose their epithelial status as well as apicobasal polarity sustained by cell–cell adhesion molecules and gain mesenchymal traits. EMT is a dynamic process that converts epithelial cancer cells to dedifferentiated cells with additional mesenchymal properties. This transition entails up- and down-regulation of different proteins responsible for profound cellular reorganization resulting in the acquisition of enhanced migratory and invasive properties.[9,10] By facilitating tumor cell invasion and dissemination to distant organs, EMT has emerged as a key regulator of metastasis.

Paired-related homeobox 1 (PRRX1) is a novel EMT inducer, and its expression is associated with metastasis and prognosis in multiple tumors, participating in cancer progression in two different manners. Specifically, PRRX1 overexpression induces EMT in tumor cells, and it is also an indicator of a poor prognosis in gastric cancer and colorectal cancer.[11,12] Moreover, tumor cells acquire cancer stem cell (CSC)-like properties due to loss of PRRX1 expression, which results in distant metastasis and indicates a poor prognosis in breast cancer and hepatocellular carcinoma.[13] The function of PRRX1 in CCRCC, however, has not yet been elucidated.

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified endogenous protein phosphatase 2A (PP2A) inhibitor in human malignancies.[14] Overexpression of CIP2A has been detected in multiple malignancies, such as gastric cancer, breast cancer, prostate cancer, lung cancer, papillary thyroid carcinoma and head and neck squamous cell carcinoma,[15,16,17] and the clinical relevance of CIP2A overexpression suggests its use as a prognostic marker in cancer patients. Indeed, CIP2A plays an important role in the occurrence and development of various malignant tumors.

Overall, studies on VM, PRRX1 and CIP2A in relation to metastasis and prognosis have indicated that these biomarkers influence tumor development. Nonetheless, associations between VM, PRRX1 and CIP2A in CCRCC have not yet been extensively reported. The purpose of this study was to explore the hypothesis that these biomarkers are mutually associated with metastasis and prognosis in CCRCC.

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2 Materials and methods

2.1 Specimens

A total of 110 CCRCC tissues and surrounding “normal” nephron tissues were collected from the Department of Pathology of the First Affiliated Hospital of Bengbu Medical College (China) from January 2010 to December 2012. All patients underwent radical resection and lymph node dissection (patients who underwent any preoperative anticancer therapy were excluded). The “normal” nephron tissues were obtained from the same patients and from surrounding nephron tissues at least 5 cm away from the cancer edge. Complete demographic, pathological, and follow-up data (at 6-month intervals by mobile phone and social applications) were available for all patients. The overall survival time (OST) was calculated from the date of surgery to the date of death or December 2018 (mean OS: 12 months, range: 96 months). Written consent was obtained from all patients. The study was approved by the Ethics Committee of Bengbu Medical College and performed in accordance with the guidelines of the Declaration of Helsinki. Tumor-node-metastasis (TNM) was evaluated in accordance with the 2010 edition of the American Joint Committee on Cancer (AJCC). Tumor differentiation was assessed in accordance with World Health Organization (WHO) standards. Patient characteristics are shown in Table 1.

Table 1

Table 1

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2.2 Immunohistochemistry

Immunohistochemical staining was carried out in accordance with the instructions of EliVisionTM plus Detection Kit (Lab Vision, Fremont, CA). All CCRCC and corresponding “normal” nephron tissues were fixed in 10% buffered formalin and then embedded in paraffin, and continuous 4-μm-thick sections were cut. The samples were deparaffinized using routine methods and dehydrated using xylene and alcohol. Methanol containing 3% H2O2 solution was used to block endogenous peroxidase activity, and citrate buffer was used to retrieve antigens. All sections were then washed several times with phosphate-buffered saline (PBS) and blocked with goat serum at room temperature for 30 min. After washing with PBS, all sections were incubated with a mouse monoclonal antibody against human PRRX1 (OriGene, Rockville, MD) or CIP2A (Abcam, San Francisco, CA) at 37°C for 1 h. Periodic-acid-Schiff (PAS)-CD34 dual staining was used to identify endothelial cells in the glycosylated basement membranes of vessels, including vessel-like (VM) structures. Finally, all sections were counterstained with hematoxylin, dehydrated, air-dried, and mounted.

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2.3 Evaluation of staining

All staining results were evaluated semiquantitatively by two experienced pathologists who were blinded to the patients’ clinical information and follow-up data. To avoid potential intratumoral heterogeneity of antibody expression, we analyzed ten representative high-power-fields (HPF) from different areas of each CCRCC slide. The experimental results were scored according to the intensity (no staining, 0; weak staining, 1; moderate staining, and 2; strong staining, 3) and extent (<11% positive cells, 1; 11–50% positive cells, 2; 51–75% positive cells, 3; and >75% positive cells, 4) of staining.[8,27,28,29] Final scores were obtained by multiplying the intensity and extent scores, which ranged from 0–12. Final scores ≥3 were considered positive. A modified Yue and Chen method was used to assess VM in the CCRCC tissues and control tissues.[18] For tissue sections that were positive for all three factors (VM, PRRX1, and CIP2A), the average value of the final score of each tissue section was used.

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2.4 Statistical analysis

All data were analyzed using SPSS 24.0 software (IBM, New York, NY). Relationships between clinicopathological indices and VM, PRRX1 and CIP2A were analyzed using Fisher's exact test or the chi-square test. Association between VM, PRRX1, and CIP2A was evaluated using Spearman's correlation test. The effects of VM, PRRX1 and CIP2A on survival were analyzed by univariate and multivariate analyses. Univariate OST analysis was carried out using the Kaplan–Meier method with the log-rank test, and multivariate OST analysis using the Cox regression model. P < .05 was considered indicative of statistically significant differences.

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3 Results

3.1 Associations between VM, PRRX1, and CIP2A in the cancer tissues of patients and clinicopathological characteristics

To assess the effects of VM, PRRX1, and CIP2A in CCRCC, we immunohistochemically detected these factors in both CCRCC and corresponding normal renal tissue specimens. Clinicopathological characteristics were compared to these experimental data. The rate of VM positivity (small vessel structure, which is a lumen-like structure in CCRCC; the lumen was PAS-positive but CD34-negative; the VM structural pattern included, e.g., linear, tubular, network aspects) was significantly higher in the CCRCC specimens (42.7%, 47/110) than in the corresponding normal tissues (0%, 0/110, P < .001; Fig. 1A and B). Moreover, the rate of VM structure development in CCRCC was positively related to tumor pathological grade, size, vascular invasion, lymph node metastasis (LNM) stage, and TNM stage but not to patient age, sex, smoking status or location (Table 2).

Figure 1

Figure 1

Table 2

Table 2

PRRX1 expression was lower in CCRCC tissues (64.5%, 71/110) than in control tissues (10.2%, 11/110; P < .001; Fig. 1C and D). Lack of PRRX1 expression was significantly associated with tumor grade, size, vascular invasion, LNM stage, and TNM stage. No correlation was found between PRRX1 expression and patient sex, age, smoking status or location (Table 2).

Similar to VM and PRRX1, CIP2A expression was significantly higher in CCRCC tissues (55.0%, 55/110) than in control kidney tissues (5.5%, 6/110; P < .001; Fig. 1E and F). CIP2A expression in CCRCC was related to tumor grade, size, vascular invasion, LNM stage and TNM stage but not to patient sex, age, smoking status or location (Table 2).

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3.2 Univariate and multivariate analyses

Follow-up data suggested that OST was significantly shorter in CCRCC patients with VM+ specimens (48.62 ± 16.362 months) than in those with VM- specimens (71.25 ± 13.183 months; log-rank = 47.583, P < .001; Fig. 2A). Similarly, the OST of PRRX1- patients (54.06 ± 16.941 months) was significantly shorter than that of PRRX1+ patients (75.28 ± 11.978 months; log-rank = 31.322, P < .001; Fig. 2B). The OST of CIP2A +patients (50.02 ± 15.849 months) was significantly shorter than that of CIP2A- patients (73.15 ± 12.626 months; log-rank = 55.886, P < .001; Fig. 2C). In univariate analysis, the OST time was significantly related to clinicopathological information, including tumor size (log-rank = 37.409, P < .001, Fig. 2D), grade (log-rank = 86.590, P < .001, Fig. 2E), vascular invasion (log-rank = 86.598, P < .001, Fig. 2F), LNM stage (log-rank = 84.67, P < .001, Fig. 2G) and TNM stage (log-rank = 126.649, P < .001, Fig. 2H) (Table 3).

Figure 2

Figure 2

Table 3

Table 3

Moreover, multivariate analysis demonstrated that VM+, CIP2A+, PRRX1- specimens, tumor grade, TNM stage, and LNM were independent prognostic factors for CCRCC (Table 4).

Table 4

Table 4

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3.3 Correlation among VM and expression of CIP2A and PRRX1 in CCRCC

Spearman correlation coefficient analysis indicated negative correlations between PRRX1+ expression and VM (r = −0.333, P < .001) and CIP2A (r = −0.513, P < .001), though expression of CIP2A was positively associated with VM development (r = 0.349, P < .001) (Table 5).

Table 5

Table 5

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4 Discussion

CCRCC represents the most aggressive subtype of kidney cancer and poses a serious threat to human health.[19] However, the clinical prognosis of CCRCC is influenced by progression, covering a complex network of gene interactions. As biomarkers for early detection and follow-up of the disease are not currently available, it is necessary to investigate the pathogenic mechanism of the molecular field of renal malignancy and the comprehensive utilization of biological markers for clinical diagnosis and treatment.

A large number of experimental studies have confirmed that activation of EMT can promote the invasion and migration of tumor cells. In addition, many molecules have been confirmed to be involved in EMT and to participate in this process through a certain signal transduction pathway.[20,21] EMT can promote the formation of VM through different signaling pathways, with related transcription factors including Twist1, ZEB1, Snail, and Slug.[22–25] EMT can also induce the formation of VM in tumor cells under hypoxia, which has a synergistic effect and is closely related to the biological behavior of tumor invasiveness and increased death rates for tumor patients.[26] In our research, we found that VM was positively correlated with CCRCC grade, tumor size, LNM stage, and TNM stage. Moreover, Kaplan-Meier survival analysis indicated that VM+ CCRCC patients had a significantly shorter OST than did VM- patients. Compared with malignant tumor patients without VM, patients with VM had a worse prognosis. Our study is consistent with previous studies.[4,8,27,28]

Expression of the transcription factor PRRX1 as a transcription factor is related to embryonic limb development, vascular differentiation and skeletal muscle development,[30,31] and it has been suggested that transforming growth factor-b and microRNA regulate expression of PRRX1.[32–34] However, details are lacking and further analysis is required to uncover the signaling network regulating PRRX1. In this study, we observed that the level of PRRX1 expression was lower in CCRCC tissues than in adjacent tissues. Furthermore, low expression was associated with tumor progression and poor prognosis in CCRCC, as based on an analysis of clinicopathological variables, and the OST of PRRX1- patients was significantly shorter than that of PRRX1+ patients. Our results are consistent with those from previous studies.[35–37] According to our results, we speculate that PRRX1 likely acts as a bidirectional regulatory factor in diverse cancer types and that PRRX1 may act as a tumor suppressor in CCRCC.

CIP2A inhibits the activity of PP2A and thus maintains the malignant phenotype of tumor cells and plays an important role in the occurrence, development and biological behavior of tumor cells. CIP2A (cancerous Inhibitor of PP2A) is an important oncogene. PP2A is a potent tumor inhibitor that acts on a variety of carcinogenic transcription factors, including MYC, beta-catenin, AKT and BCL2 dephosphorylation and degradation,[38,39] and CIP2A has been shown to decrease cancer cell viability and anchorage-independent growth and to induce apoptosis.[40] In our study, we found that CIP2A was significantly overexpressed in the majority of CCRCC tissues compared with control tissues. CIP2A expression was positively related to tumor grade, tumor size, LNM stage, and TNM stage. Moreover, Kaplan-Meier survival curve analysis demonstrated that CIP2A+ CCRCC patients had a significantly shorter OST than did CIP2A- patients. Our results are similar to those from other studies.[41–43]

In conclusion, our research data show that VM, PRRX1 and CIP2A can be used as a biological reference index for the clinical prognosis of renal clear cell carcinoma. It is acknowledged that adhesion molecules and other factors that modulate the EMT process can regulate VM formation. PRRX1 and CIP2A are major EMT inducers that play a predominate role in tumors progress via several signaling pathways and may become therapeutic targets for intervention in CCRCC. Nonetheless, further study is required to clarify the mechanism involved. Our present research results provide some reference data for the diagnosis and prognosis of renal cell carcinoma. Due to the limited number of clinical samples and the uncertainty of follow-up results as well as the relatively simple experimental content, a large number of cytological and animal experiments are required to verify the use of PRRX1, CIP2A, and VM as effective markers in renal cell carcinoma.

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5 Conclusions

We examined the roles of VM, PRRX1 and CIP2A in CCRCC. Low PRRX1 expression combined with high VM and CIP2A was associated with metastasis and a poor prognosis in CCRCC. Furthermore, VM, PRRX1 and CIP2A might serve as valuable biomarkers in CCRCC, and the comprehensive detection of VM, PRRX1 and CIP2A may be valuable for indicating prognosis in CCRCC. It has certain clinical significance for the treatment of CCRCC.

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Author contributions

Conceptualization: Shiwu Wu.

Data curation: Xiaolin Wang, Ruixue Yang, Qi Wang.

Formal analysis: Xiaolin Wang.

Funding acquisition: Shiwu Wu.

Investigation: Xiaolin Wang.

Methodology: Xiaolin Wang, Ruixue Yang.

Resources: Xiaolin Wang.

Software: Xiaolin Wang, Ruixue Yang, Yichao Wang, Hongfei Ci.

Supervision: Shiwu Wu.

Writing – original draft: Xiaolin Wang.

Writing – review & editing: Shiwu Wu.

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[1]. Znaor A, Lortet-Tieulent J, Laversanne M, et al. International variations and trends in renal cell carcinoma incidence and mortality. Eur Urol 2015;67:519–30.
[2]. Gudbjartsson T, Hardarson S, Petursdottir V, et al. Histological subtyping and nuclear grading of renal cell carcinoma and their implications for survival: a retrospective nation-wide study of 629 patients. Eur Urol 2005;48:593–600.
[3]. Maniotis AJ, Folberg R, Hess A, et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol 1999;155:739–52.
[4]. EI Hallani S, Boisselier B, Peglion F, et al. A new alternative mechanism in glioblastoma vascularization: tubular vasculogenic mimicry. Brain 2010;133:973–82.
[5]. Zhang S, Guo H, Zhang D, et al. Microcirculation patterns in different stages of melanoma growth. Oncol Rep 2006;15:15–20.
[6]. Sun W, Fan YZ, Zhang WZ, et al. A pilot histomorphology and hemodynamic of vasculogenic mimicry in gallbladder carcinomas in vivo and in vitro. J Exp Clin Cancer Res 2011;16:30–46.
[7]. Zhao N, Sun BC, Zhao XL, et al. Role of Bcl-2 and its associated miRNAs in vasculogenic mimicry of hepatocellular carcinoma. Int J Clin Exp Pathol 2015;8:15759–68.
[8]. Wu S, Yu L, Wang D, et al. Aberrant expression of CD133 in non-small cell lung cancer and its relationship to vasculogenic mimicry. BMC Cancer 2012;12:535.
[9]. Nieto MA, et al. The ins and outs of the epithelial to mesenchymal transition in health and disease. Annu Rev Cell Dev Biol 2011;27:347–76.
[10]. Thiery JP, Acloque H, Huang RY, et al. Epithelial-mesenchymal transitions in development and disease. Cell 2009;139:871–90.
[11]. Guo J, Fu Z, Wei J, et al. PRRX1 promotes epithelial-mesenchymal transition through the Wnt/beta-catenin pathway in gastric cancer. Med Oncol 2015;32:393.
[12]. Takahashi Y, Sawada G, Kurashige J, et al. Paired related homoeobox 1, a new EMT inducer, is involved in metastasis and poor prognosis in colorectal cancer. Br J Cancer 2013;109:307–11.
[13]. Hirata H, Sugimachi K, Takahashi Y, et al. Downregulation of PRRX1 confers cancer stem cell-like properties and predicts poor prognosis in hepatocellular carcinoma. Ann Surg Oncol 2015;22:S1402–9.
[14]. Junttila MR, Puustinen P, Niemela M, et al. CIP2A inhibits PP2A in human malignancies. Cell 2007;130:51–62.
[15]. Khanna A, Bockelman C, Hemmes A, et al. MYC-dependent regulation and prognostic role of CIP2A in gastric cancer. J Natl Cancer Inst 2009;101:793–805.
[16]. Yu G, Liu G, Dong J, et al. Clinical implications of CIP2A protein expression in breast cancer. Med Oncol 2013;30:524.
[17]. Cristobal I, Rojo F, Madoz-Gurpide J, et al. Cross talk between Wnt/beta-catenin and CIP2A/Plk1 signaling in prostate cancer: promising therapeutic implications. Mol Cell Biol 2016;36:1734–9.
[18]. Yue WY, Chen ZP, et al. Does vasculogenic mimicry exist in astrocytoma? J Histochem Cytochem 2005;53:997–1002.
[19]. Rini BI, Campbell SC, Escudier B, et al. Renal cell carcinoma. Lancet 2009;373:1119–32.
[20]. Chaffer CL, San Juan BP, Lim E, et al. EMT, cell plasticity and metastasis. Cancer Metastasis Rev 2016;35:645–54.
[21]. Lambert AW, Pattabiraman DR, Weinberg RA, et al. Emerging biological principles of metastasis. Cell 2017;168:670–91.
[22]. Ma JL, Han SX, Zhu Q, et al. Role of Twist in vasculogenic mimicry formation in hypoxic hepatocellular carcinoma cells in vitro. Biochem Biophys Res Commun 2011;408:686–91.
[23]. Dohadwala M, Wang G, Heinrich E, et al. The role of ZEB1 in the inflammationinduced promotion of EMT in HNSCC. Otolaryngol Head Neck Surg 2010;142:753–9.
[24]. Evdokimova V, Tognon C, Ng T, et al. Translational activation of Snail1 and other developmentally regulated transcription factors by YB-1 promotes an epithelialmesenchymal transition. Cancer Cell 2009;15:402–15.
[25]. Maria K, Spandidos DA, Apostolos Z, et al. Epithelial-mesenchymal transition-associated miRNAs in ovarian carcinoma, with highlight on the miR-200 family: prognostic value and prospective role in ovarian cancer therapeutics. Cancer Lett 2014;351:173–81.
[26]. Du J, Sun B, Zhao X, et al. Hypoxia promotes vasculogenic mimicry formation by inducing epithelial-mesenchymal transition in ovarian carcinoma. Gynecol Oncol 2014;133:575–83.
[27]. Ci H, Xu Z, Wu S, et al. Expressions of KAI1 and E-cadherin in nonsmall cell lung cancer and their correlation with vasculogenic mimicry. Medicine (Baltimore) 2018;97:e12293.
[28]. Wang Y, Yang R, Wang X, et al. Evaluation of the correlation of vasculogenic mimicry, Notch4, DLL4, and KAI1/CD82 in the prediction of metastasis and prognosis in non-small cell lung cancer. Medicine (Baltimore) 2018;97:e13817.
[29]. Chai DM, Qin YZ, Wu SW, et al. WISP2 exhibits its potential antitumor activity via targeting ERK and E-cadherin pathways in esophageal cancer cells. J Exp Clin Cancer Res 2019;38:102.
[30]. Higuchi M, Kato T, Chen M, et al. Temporospatial gene expression of Prx1 and Prx2 is involved in morphogenesis of cranial placode-derived tissues through epithelio-mesenchymal interaction during rat embryogenesis. Cell Tissue Res 2013;353:27–40.
[31]. He B, Lin X, Tian F, et al. MiR-133a-3p inhibits oral squamous cell carcinoma (OSCC) proliferation and invasion by suppressing COL1A1. J Cell Biochem 2018;119:338–46.
[32]. Yang D, Sun Y, Hu L, et al. Integrated analyses identify a master microRNA regulatory network for the mesenchymal subtype in serous ovarian cancer. Cancer Cell 2013;23:186–99.
[33]. Ocaña OH, Córcoles R, Fabra A, et al. Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 2012;22:709–24.
[34]. Jiang J, Zheng M, Zhang M, et al. PRRX1 regulates cellular phenotype plasticity and dormancy of head and neck squamous cell carcinoma through miR-642b-3p. Neoplasia 2019;21:216–29.
[35]. Zhi-Dong LV, Bin Kong, Xiang-Ping Liu, et al. miR-655 suppresses epithelial-to-mesenchymal transition by targeting Prrx1 in triple-negative breast cancer. J Cell Mol Med 2016;20:864–73.
[36]. Zhi-Dong LV, Zhao-Chuan Yang, Xiang-Ping Liu, et al. Silencing of Prrx1b suppresses cellular proliferation, migration, invasion and epithelial-mesenchymal transition in triple-negative breast cancer. J Cell Mol Med 2016;20:1640–50.
[37]. Hongbin Zhu, Gengyun Sun. Loss of PRRX1 induces epithelial-mesenchymal transition and cancer stem cell-like properties in A549 cells. Am J Transl Res 2017;9:1641–50.
[38]. Westermarck J, Hahn WC. Multiple pathways regulated by the tumor suppressor PP2A in transformation. Trends Mol Med 2008;14:152–60.
[39]. Perrotti D, Neviani P. Protein phosphatase 2A: a target for anticancer therapy. Lancet Oncol 2013;14:e229–38.
[40]. Côme C, Laine A, Chanrion M, et al. CIP2A is associated with human breast cancer aggressivity. Clin Cancer Res 2009;15:5092–100.
[41]. Qizhen Tang, Qifei Wang, Guang Zeng, et al. Overexpression of CIP2A in clear cell renal cell carcinoma promotes cellular epithelial-mesenchymal transition and is associated with poor prognosis. Oncol Rep 2015;34:2515–22.
[42]. Bo Penga, Ningjing Leia, Yurong Chaia, et al. CIP2A regulates cancer metabolism and CREB phosphorylation in non-small cell lung cancer. Mol Biosyst 2015;11:105–14.
[43]. Flørenes VA, Emilsen E, Dong HP, et al. Cellular localization of CIP2A determines its prognostic impact in superficial spreading and nodular melanoma. Cancer Med 2015;4:903–13.

CIP2A; clear cell renal cell carcinoma; EMT; PRRX1; VM

Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.