The metastasis suppressor CD82/KAI1 represses the TGF‐β₁ and Wnt signalings inducing epithelial‐to‐mesenchymal transition linked to invasiveness of prostate cancer cells

Abstract

Background The epithelial‐to‐mesenchymal transition (EMT) is closely associated with cancer invasion and metastasis. Since the transforming growth factor β (TGF‐β) and Wnt signals induce EMT in various epithelial cell types, we examined whether and how the CD82/KAI1 metastasis suppressor affects the TGF‐β and Wnt signal‐dependent EMT in human prostate cancer cells. Methods The invasiveness of cancer cells was evaluated by examining their ability to pass through the basement membrane matrigel. The subcellular localizations of Smad4 and β‐catenin proteins were respectively examined by confocal microscopy following immunofluorescence antibody staining and immunoblotting analysis following subcellular fractionation. The transcriptional activities of the TGF‐β1‐responsive TRE and Wnt‐responsive Tcf/Lef promoters were determined by a luciferase reporter assay following transfection of the recombinant reporter vector into the cell. Results TGF‐β1 and Wnt3a treatments of human prostate cancer cells without CD82 expression resulted in not only increased invasiveness but also EMT involving the development of motile structures, downregulation of E‐cadherin, and upregulation of the mesenchymal proteins. However, in the cells with high levels of CD82, the TGF‐β1 and Wnt3a stimulations neither elevated invasiveness nor induced EMT. Furthermore, the TGF‐β1 signaling events occurring in the CD82‐deficient cells, such as phosphorylation of Smad2, nuclear translocation of Smad4, and transactivation of the TRE promoter, did not take place in the high CD82‐expressing cells. Further, high CD82 expression interfered with the Wnt signal‐dependent alterations in the phosphorylation pattern of glycogen synthase kinase 3β (GSK‐3β) in prostate cancer cells, which allowed GSK‐3β to continue phosphorylating β‐catenin, thereby attenuating the Wnt signaling effects on the nuclear translocation of β‐catenin and subsequent transactivation of the Tcf/Lef promoter. Conclusions The results of the present study suggest that CD82/KAI1 functions in suppressing TGF‐β1‐ and Wnt‐induced EMT in prostate cancer cells by inhibiting the TGF‐β1/Smad and Wnt/β‐catenin pathways. Therefore, loss or decrease of CD82 expression is likely to render prostate cancer cells prone to respond to the TGF‐β1 and Wnt signals with EMT, resulting in the development of a motile and invasive mesenchymal phenotype related to the initiation of the metastatic cascade.

miR-20b-5p, TGFBR2, and E2F1 Form a Regulatory Loop to Participate in Epithelial to Mesenchymal Transition in Prostate Cancer

“…A number of recent studies have reported on the progression of PCa and EMT in TGF-β1 regulating PCa cells (43)(44)(45)(46). However, in the present study, we found that the auto-regulatory axis miR-20b-5p/TGFBR2/E2F1, which is regulated by TGF-β1, is involved in PCa development and progression through regulating EMTrelated gene expression.…”

The Context-Dependent Impact of Integrin-Associated CD151 and Other Tetraspanins on Cancer Development and Progression: A Class of Versatile Mediators of Cellular Function and Signaling, Tumorigenesis and Metastasis

“…Also, the genes that regulate cell proliferation, survival, and metabolism (e.g., Cyclin D1 and Myb ) are strongly affected [ 127 ]. Additionally, expression of the genes involved in regulation of the stability of E-cadherin/β-catenin complexes appeared suppressed, strengthening the intrinsic role of CD151 in cell-cell adhesion [ 34 , 116 , 117 , 137 ]. In contrast, CD151 disruption markedly blunts survival of epithelial basal cell-derived tumor cells [ 28 ], consistent with the impact of CD151 knockdown on MDA-MB-231 cells [ 38 , 71 ].…”

“…Intriguingly, there is growing evidence that many tetraspanins such as CD151 and CD82 can negatively or positively influence tumor development and metastasis in oncogenic context- and cell lineage-dependent manners, where they regulate strength of cell-cell junctions, signal transduction of the Wnt pathway, the epithelial-mesenchymal transition (EMT), maintenance of cancer stem cells (CSCs), and dynamics of exosomes ( Table 1 ) [ 20 , 21 , 28 , 33 , 34 , 35 ]. This emerging paradigm presents a challenge to conceptualize functional and signaling roles of the tetraspanin family in human cancer, and their utilities as biomarkers and drug targets for cancer diagnosis and treatment.…”

The Prospect of Identifying Resistance Mechanisms for Castrate-Resistant Prostate Cancer Using Circulating Tumor Cells: Is Epithelial-to-Mesenchymal Transition a Key Player?

“…IFN-c can induce epithelial-tomesenchymal transition (EMT) in PCa cells via the JAK-STAT signaling pathway [75], and STAT3 may directly mediate EMT progression and regulate ZEB1 expression in CRC [76] PCa progression, cell proliferation, and inhibition of apoptosis [51,52] No direct analysis of these pathways in CTCs Wnt/ β-catenin Dysregulation of Wnt/β-catenin signaling has been implicated in the development of cancer in different tissues such as lung, skin, liver, and prostate [52], via regulating Zeb1 in CRC [77] Wnt/β-catenin pathway promotes the metastatic spread of prostate cancer cells by inducing EMT [78] Epithelial type CTCs and activation of Wnt/β-catenin signaling in lung cancer cells [79]. No report in PCa CTCs Notch Crosstalk between the Jagged1/Notch and JAK/STAT3 signaling pathways by promoting EMT through Jagged-1 in ovarian cancer [80] Notch signaling results in prostate tumor recurrence via EMT [81] Increased production of ROS results in the upregulation of Notch1 in CTCs in metastatic breast and melanoma cancer [82].…”