Vasculogenic mimicry in bladder cancer and its association with the aberrant expression of ZEB1

Abstract

Abstract. The aim of the present study was to investigate the associations between vasculogenic mimicry (VM) and zinc finger E-box binding homeobox 1 (ZEB1) in bladder cancer. VM structure and ZEB1 expression were analyzed by cluster of differentiation 34/periodic acid Schiff (PAS) double staining and immunohistochemical staining in 135 specimens from patients with bladder cancer, and a further 12 specimens from normal bladder tissues. Three-dimensional (3-D) culture was used to detect VM formation in the bladder transitional cancer cell lines UM-UC-3 and J82, and the immortalized human bladder epithelium cell line SV-HUC-1 in vitro. ZEB1 expression in these cell lines was compared by reverse transcription-quantitative polymerase chain reaction and western blot assays. In addition, small interfering RNA was used to inhibit ZEB1 in UM-UC-3 and J82 cells, followed by 3-D culturing of treated cell lines. As a result, VM was observed in 31.1% of specimens from bladder cancer tissues, and cases with high ZEB1 expression accounted for 60.0% of patients with bladder cancer. In addition, ZEB1 expression was closely associated with VM (r=0.189; P<0.05), and also increased as the grade and stage of the tumor developed. In an in vitro assay, UM-UC-3 and J82 cells exhibited VM formation, however, SV-HUC-1 did not. Furthermore, VM-forming cancer cell lines UM-UC-3 and J82 exhibited higher ZEB1 expression. Notably, VM formation was inhibited following knockdown of ZEB1. In conclusion, ZEB1 may be associated with VM in bladder cancer and serve an important role in the process of VM formation. However, its detailed mechanism requires further study.

<p>Osteoglycin (OGN) Inhibits Cell Proliferation and Invasiveness in Breast Cancer via PI3K/Akt/mTOR Signaling Pathway</p>

“…The ZEB transcription factor family acts by binding to the cadherin promoter region 39,40. ZEB1 promotes the formation of angiogenesis and induces EMT in bladder cancer 41. The transformation of epithelial cells into mesenchymal cells is accompanied by an increase in cancer stemness, metastatic ability, and drug resistance 42.…”

Identification and analysis of long non-coding RNA related miRNA sponge regulatory network in bladder urothelial carcinoma

“…Several studies have demonstrated that ZEB1 was significantly overexpressed in bladder cancer tissues compared to normal healthy adjacent tissues [36]. Li et al [37] reported that ZEB1 was significantly overexpressed in bladder cancers compared to normal tissues, and played a crucial role during VM formation, and was closely associated with invasion, metastasis and poor prognosis of malignant tumors [38, 39]. Transmembrane protein 100 (TMEM100), located at 17q32, was first identified as a transcript in the mouse genome.…”

Fact or Fiction, It Is Time for a Verdict on Vasculogenic Mimicry?

“…For example, some studies postulate the presence of VM based on a luminal space in a carcinoma cross-section, however no PAS+ border is present (16). Similarly, weak PAS staining always leaves the doubt of whether a membrane is present or the structure is in fact a blood pool (17–20). In contrast, several reports from the group of Sun and colleagues clearly demonstrate the presence of PAS+/CD31- structures that contain RBCs in both Hepatocarcinoma and Gastro Intestinal Stromal Tumor (GIST) patients (14, 21).…”

“…The literature on in vitro VM models contains several attempts for a quantification method. Such studies have employed a variety of methods including: tubule length, number of structures, tubular structure connections, or PAS+ levels (16, 17, 60–62). However, as explained above most studies have failed to demonstrate these tubular structures are indeed functional (i.e., have a fluid-conducting lumen) therefore the validity of these methods remains questionable.…”