148 STROMAL CELLS OF RENAL CELL CARCINOMA REPRESENT MESENCHYMAL STEM CELL-LIKE CELLS, PROMOTE EPITHELIAL-MESENCHYMAL-TRANSITION AND TUMOR FORMATION

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of kidney cancer. We previously reported that CD105(+) subpopulation in human ccRCC tumors possesses tumor cell self-renewal and chemoresistance capability. In this study, we showed that CD105(+) ACHN tumor cells exhibit epithelial mesenchymal transition (EMT) phenotype with high expression of mesenchymal marker N-cadherin and low expression of epithelial marker E-cadherin. They are more motile and invasive compared to the unselected parental ACHN tumor cells. The knockdown of CD105 by RNA interference led to the downregulation of N-cadherin and the upregulation of E-cadherin and reduced motility and invasiveness of CD105(+) cells. Overexpression of stem cell factor MYC in CD105 knocked down cells increased mesenchymal markers and cell motility. However, the CD105(+) population of tumor cells does not exhibit an increase metastatic potential in vivo. Findings from this study support that CD105 plays a functional role in maintaining cancer stem cell and EMT phenotype, with MYC as a common mediator for both of these traits. Our work suggests that the ability to metastasize does not coincide with the cancer stem cell or EMT function of CD105.

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TNF-α Induces Epithelial–Mesenchymal Transition of Renal Cell Carcinoma Cells via a GSK3β-Dependent Mechanism

Molecular Cancer Research ◽

10.1158/1541-7786.mcr-12-0160 ◽

2012 ◽

Vol 10 (8) ◽

pp. 1109-1119 ◽

Cited By ~ 71

Author(s):

Ming-Yi Ho ◽

Shye-Jye Tang ◽

Mei-Jen Chuang ◽

Tai-Lung Cha ◽

Jing-Yao Li ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Epithelial Mesenchymal Transition ◽

Carcinoma Cells ◽

Mesenchymal Transition ◽

Tnf Α ◽

Dependent Mechanism

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Knockdown of NSD2 Suppresses Renal Cell Carcinoma Metastasis by Inhibiting Epithelial-Mesenchymal Transition

International Journal of Medical Sciences ◽

10.7150/ijms.36128 ◽

2019 ◽

Vol 16 (10) ◽

pp. 1404-1411 ◽

Cited By ~ 3

Author(s):

Xu Han ◽

Lianhua Piao ◽

Xiaofeng Yuan ◽

Luhui Wang ◽

Zhiwei Liu ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Renal Cell Carcinoma Metastasis ◽

Carcinoma Metastasis

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Regulation of Oncogenic Targets by the Tumor-Suppressive miR-139 Duplex (miR-139-5p and miR-139-3p) in Renal Cell Carcinoma

Biomedicines ◽

10.3390/biomedicines8120599 ◽

2020 ◽

Vol 8 (12) ◽

pp. 599

Author(s):

Reona Okada ◽

Yusuke Goto ◽

Yasutaka Yamada ◽

Mayuko Kato ◽

Shunichi Asai ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Epithelial Mesenchymal Transition ◽

Ectopic Expression ◽

Molecular Pathogenesis ◽

Molecular Networks ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Passenger Strand

We previously found that both the guide and passenger strands of the miR-139 duplex (miR-139-5p and miR-139-3p, respectively) were downregulated in cancer tissues. Analysis of TCGA datasets revealed that low expression of miR-139-5p (p < 0.0001) and miR-139-3p (p < 0.0001) was closely associated with 5-year survival rates of patients with renal cell carcinoma (RCC). Ectopic expression assays showed that miR-139-5p and miR-139-3p acted as tumor-suppressive miRNAs in RCC cells. Here, 19 and 22 genes were identified as putative targets of miR-139-5p and miR-139-3p in RCC cells, respectively. Among these genes, high expression of PLXDC1, TET3, PXN, ARHGEF19, ELK1, DCBLD1, IKBKB, and CSF1 significantly predicted shorter survival in RCC patients according to TCGA analyses (p < 0.05). Importantly, the expression levels of four of these genes, PXN, ARHGEF19, ELK1, and IKBKB, were independent prognostic factors for patient survival (p < 0.05). We focused on PXN (paxillin) and investigated its potential oncogenic role in RCC cells. PXN knockdown significantly inhibited cancer cell migration and invasion, possibly by regulating epithelial–mesenchymal transition. Involvement of the miR-139-3p passenger strand in RCC molecular pathogenesis is a new concept. Analyses of tumor-suppressive-miRNA-mediated molecular networks provide important insights into the molecular pathogenesis of RCC.

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High levels of intratumor heterogeneity characterize the expression of epithelial-mesenchymal transition markers in high-grade clear cell renal cell carcinoma

Annals of Diagnostic Pathology ◽

10.1016/j.anndiagpath.2018.01.001 ◽

2018 ◽

Vol 34 ◽

pp. 27-30 ◽

Cited By ~ 4

Author(s):

Rosa Guarch ◽

Charles H. Lawrie ◽

Gorka Larrinaga ◽

Javier C. Angulo ◽

Rafael Pulido ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Epithelial Mesenchymal Transition ◽

Intratumor Heterogeneity ◽

High Grade ◽

Cell Renal Cell Carcinoma ◽

Mesenchymal Transition

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Role of Nuclear Claudin-4 in Renal Cell Carcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms21218340 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8340

Author(s):

Takuya Owari ◽

Takamitsu Sasaki ◽

Kiyomu Fujii ◽

Rina Fujiwara-Tani ◽

Shingo Kishi ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Tight Junction ◽

Cell Carcinoma ◽

Renal Cell ◽

Nuclear Translocation ◽

Epithelial Mesenchymal Transition ◽

Nuclear Fraction ◽

Mesenchymal Transition ◽

Junction Protein

Claudin-4 (CLDN4) is a tight junction protein to maintain the cancer microenvironment. We recently reported the role of the CLDN4 not forming tight junction in the induction of epithelial-mesenchymal transition (EMT). Herein, we investigated the role of CLDN4 in renal cell carcinoma (RCC), focusing on CLDN4. CLDN4 expression in 202 RCCs was examined by immunostaining. CLDN4 phosphorylation and subcellular localization were examined using high metastatic human RCC SN12L1 and low metastatic SN12C cell lines. In 202 RCC cases, the CLDN4 expression decreased in the cell membrane and had no correlation with clinicopathological factors. However, CLDN4 was localized in the nucleus in 5 cases (2%), all of which were pT3. Contrastingly, only 6 of 198 nuclear CLDN4-negative cases were pT3. CLDN4 was found in the nuclear fraction of a highly metastatic human RCC cell line, SN12L1, but not in the low metastatic SN12C cells. In SN12L1 cells, phosphorylation of tyrosine and serine residues was observed in cytoplasmic CLDN4, but not in membranous CLDN4. In contrast, phosphorylation of serine residues was observed in nuclear CLDN4. In SN12L1 cells, CLDN4 tyrosine phosphorylation by EphA2/Ephrin A1 resulted in the release of CLDN4 from tight junction and cytoplasmic translocation. Furthermore, protein kinase C (PKC)-ε phosphorylated the CLDN4 serine residue, resulting in nuclear import. Contrarily, in SN12C cells that showed decreased expression of EphA2/Ephrin A1 and PKCε, the activation of EphA2/EphrinA1 and PKCε induced cytoplasmic and nuclear translocation of CLDN4, respectively. Furthermore, the nuclear translocation of CLDN4 promoted the nuclear translocation of Yes-associated protein (YAP) bound to CLDN4, which induced the EMT phenotype. These findings suggest that the release of CLDN4 by impaired tight junction might be a mechanism underlying the malignant properties of RCC. These findings suggest that the release of CLDN4 by impaired tight junction might be one of the mechanisms of malignant properties of RCC.

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CD103-positive CSC exosome promotes EMT of clear cell renal cell carcinoma: role of remote MiR-19b-3p

Molecular Cancer ◽

10.1186/s12943-019-0997-z ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 27

Author(s):

Lu Wang ◽

Guang Yang ◽

Danfeng Zhao ◽

Jiaqi Wang ◽

Yang Bai ◽

...

Keyword(s):

Stem Cells ◽

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Cancer Cells ◽

Lung Metastasis ◽

Renal Cell ◽

Clear Cell ◽

Epithelial Mesenchymal Transition ◽

Cell Renal Cell Carcinoma ◽

Mesenchymal Transition

Abstract Background Clear cell renal cell carcinoma (CCRCC) is characterized by a highly metastatic potential. The stromal communication between stem cells and cancer cells critically influences metastatic dissemination of cancer cells. Methods The effect of exosomes isolated from cancer stem cells (CSCs) of CCRCC patients on the progress of epithelial-mesenchymal transition (EMT) and lung metastasis of CCRCC cells were examined. Results CSCs exosomes promoted proliferation of CCRCC cells and accelerated the progress of EMT. Bioactive miR-19b-3p transmitted to cancer cells by CSC exosomes induced EMT via repressing the expression of PTEN. CSCs exosomes derived from CCRCC patients with lung metastasis produced the strongest promoting effect on EMT. Notably, CD103+ CSC exosomes were enriched in tumor cells and in lung as well, highlighting the organotropism conferred by CD103. In addition, CD103+ exosomes were increased in blood samples from CCRCC patients with lung metastasis. Conclusions CSC exosomes transported miR-19b-3p into CCRCC cells and initiated EMT promoting metastasis. CD103+ acted to guide CSC exosomes to target cancer cells and organs, conferring the higher metastatic capacity of CCRCC to lungs, suggesting CD103+ exosomes as a potential metastatic diagnostic biomarker. Graphical abstract ᅟ

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