Wnt5a / planar cell polarity signaling pathway in urothelial carcinoma, a potential prognostic biomarker

Saling, Mark; Duckett, Jordan; Ackers, Ian; Coschigano, Karen T.; Jenkinson, Scott; Malgor, Ramiro

doi:10.18632/oncotarget.15877

Cited by 9 publications

(7 citation statements)

References 34 publications

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“…In cervical cancer, CTHRC1 cooperates with E6/E7 human papillomavirus (HPV) to activate the noncanonical Wnt/PCP pathway, which aggravates tumor malignancy [ 2 ]. In pancreatic cancer and human urothelial carcinoma, Wnt5a/ROR2 signaling is associated with EMT and promotes tumor cell invasion and metastasis [ 99 , 100 ]. In GIST, CTHRC1 appears to activate the Wnt/PCP pathway in a dose-dependent manner, and Wnt5a/PCP-Rho axis determines the tumor invasion-promoting activity of CTHRC1 [ 93 ].…”

Section: Signaling Pathways Mediated By Cthrc1 Involved In the Promentioning

confidence: 99%

The Role of CTHRC1 in Regulation of Multiple Signaling and Tumor Progression and Metastasis

Mei

Zhu

Zhang

et al. 2020

Mediators of Inflammation

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Collagen triple helix repeat containing-1 (CTHRC1) has been identified as cancer-related protein. CTHRC1 expresses mainly in adventitial fibroblasts and neointimal smooth muscle cells of balloon-injured vessels and promotes cell migration and tissue repair in response to injury. CTHRC1 plays a pivotal role in some pathophysiological processes, including increasing bone mass, preventing myelination, and reversing collagen synthesis in many tumor cells. The ascended expression of CTHRC1 is related to tumorigenesis, proliferation, invasion, and metastasis in various human malignancies, including gastric cancer, pancreatic cancer, hepatocellular carcinoma, keloid, breast cancer, colorectal cancer, epithelial ovarian cancer, esophageal squamous cell carcinoma, cervical cancer, non-small-cell lung carcinoma, and melanoma. And molecules that regulate the expression of CTHRC1 include miRNAs, lncRNAs, WAIF1, and DPAGT1. Many reports have pointed that CTHRC1 could exert different effects through several signaling pathways such as TGF-β, Wnt, integrin β/FAK, Src/FAK, MEK/ERK, PI3K/AKT/ERK, HIF-1α, and PKC-δ/ERK signaling pathways. As a participant in tissue remodeling or immune response, CTHRC1 may promote early-stage cancer. Several recent studies have identified CTHRC1 as an effectual prognostic biomarker for predicting tumor recurrence or metastasis. It is worth noting that CTHRC1 has different cellular localization and mechanisms of action in different cells and different microenvironments. In this article, we focus on the advances in the signaling pathways mediated by CTHRC1 in tumors.

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Section: Signaling Pathways Mediated By Cthrc1 Involved In the Promentioning

confidence: 99%

The Role of CTHRC1 in Regulation of Multiple Signaling and Tumor Progression and Metastasis

Mei

Zhu

Zhang

et al. 2020

Mediators of Inflammation

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“…Ten gene targets of the PCP pathway, namely, CTHRC1, FZD2, FZD10, ROR2, WNT2, WNT4, WNT10B, WNT5A, WNT5B, and WNT7B, were further identified in the high leptin group ( Figure 4 C). Importantly, WNT5A and ROR2 act upstream of the PCP signaling pathway [ 19 , 20 ]. A significant correlation of both WNT5A and ROR2 ( p < 0.001, Figure 4 D) as well as another eight genes ( p < 0.001, Figure S2 ) with LEP were observed in the ccRCC cohort, indicating the potential regulatory function of leptin in activating the PCP axis.…”

Section: Resultsmentioning

confidence: 99%

Section: The Planar Cell Polarity (Pcp) Signaling Pathway Is Predictively Activated By Leptinmentioning

confidence: 89%

Leptin Is Associated with Poor Clinical Outcomes and Promotes Clear Cell Renal Cell Carcinoma Progression

et al. 2021

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Emerging evidence has shown the oncogenic roles of leptin in modulating cancer progression in addition to its original roles. Analyses of transcriptomic data and patients’ clinical information have revealed leptin’s prognostic significance in renal cell carcinoma (RCC). However, its biological effects on RCC progression have not yet been explored. Clinical and transcriptomic data of a RCC cohort of 603 patients were retrieved from The Cancer Genome Atlas (TCGA) and analyzed to reveal the correlation of leptin with clinical outcomes and the hierarchical clustering of gene signatures based on leptin levels. In addition, cox univariate and multivariate regression analyses, cell migration upon leptin treatment, identification of putative leptin-regulated canonical pathways via ingenuity pathway analysis (IPA), and the investigation of induction of Wnt5a, ROR2, and Jun N-terminal Kinases (JNK) phosphorylation activation were performed. We first observed a correlation of high leptin levels and poor outcomes in RCC patients. Knowledge-based analysis by IPA indicated the induction of cancer cell migration by leptin, which was manifested via direct leptin treatment in the RCC cell lines. In RCC patients with high leptin levels, the planar cell polarity (PCP)/JNK signaling pathway was shown to be activated, and genes in the axis, including CTHRC1, FZD2, FZD10, ROR2, WNT2, WNT4, WNT10B, WNT5A, WNT5B, and WNT7B, were upregulated. All of these genes were associated with unfavorable clinical outcomes. WNT5A and ROR2 are pivotal upstream regulators of PCP/JNK signaling, and their correlations with leptin expression levels were displayed by a Pearson correlation analysis. The inhibition of signal transduction by SP600125 reversed leptin-mediated cell migration properties in RCC cell lines. The results indicate the prognostic impact of leptin on RCC patients and uncover its ability to promote cell migration via PCP/JNK signaling.

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“…35 Many studies have reported that CTHRC1 promotes epithelial-mesenchymal transition (EMT), invasion, migration, or induce abnormal angiogenesis through multiple signaling pathways, thereby enhancing tumor cell invasion and metastasis. 30,32,[36][37][38] We believe that targeted regulation of CTHRC1 and its downstream signaling pathways might represent a potential treatment for ESCC. Wang CN et al found that PI3K-Akt and MAPK pathways were the two pathways most affected by CTHRC1 knockdown through KEGG pathway analysis.…”

Section: Dovepressmentioning

confidence: 99%

<p><em>Let-7c-5p</em> Inhibits Cell Proliferation and Migration and Promotes Apoptosis via the CTHRC1/AKT/ERK Pathway in Esophageal Squamous Cell Carcinoma</p>

Zheng¹,

Luo²,

Lü³

et al. 2020

OTT

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Purpose Let-7c-5p has been identified as a tumor suppressor in various malignancies; however, its function and mechanism in esophageal squamous cell carcinoma (ESCC) remain unclear. Here, we explored the role and potential molecular mechanism of let-7c-5p in ESCC. Materials and Methods mRNA and protein expression levels were detected by quantitative real time-polymerase chain reaction (qRT-PCR) and Western blotting. The cell counting kit-8 (CCK-8) assay was used to assess cell proliferation. Flow cytometry analysis was used to detect cell apoptosis, and cell migration was measured by wound healing assay and Transwell assays. The dual-luciferase reporter assay was used to verify the targeting relationship between let-7c-5p and CTHRC1. The tumor xenograft model was constructed to further verify the effect of let-7c-5p on the growth of ESCC in vivo. Results We found that let-7c-5p expression was downregulated in ESCC tissue and cell lines, and its reduced expression was correlated with TNM staging and lymph node metastasis. Next, we found that let-7c-5p can be used to discriminate ESCC patients from normal control subjects by receiver operating characteristic (ROC) curve analysis. Subsequently, we observed that let-7c-5p overexpression inhibited proliferation and migration and promoted apoptosis, while let-7c-5p down-regulation promoted proliferation and migration and inhibited apoptosis of TE-1 and KYSE150 cells. Furthermore, let-7c-5p overexpression inhibited tumor growth, while let-7c-5p inhibition promoted tumor growth in xenograft models. In addition, we confirmed that CTHRC1 was a direct target gene of let-7c-5p . Then, we found that let-7c-5p level was negatively correlated with CTHRC1 and negatively regulated expression of CTHRC1 in ESCC. Moreover, we confirmed that let-7c-5p upregulation significantly reduced the phosphorylation of AKT and ERK by directly inhibiting CTHRC1, while let-7c-5p downregulation showed the opposite effect. Conclusion Our findings indicate that let-7c-5p is markedly downregulated in ESCC and suppresses proliferation and migration and promotes apoptosis of ESCC cells by inhibiting the AKT and ERK signaling pathways through negatively regulating CTHRC1. Therefore, these results suggest that let-7c-5p may represent a novel biomarker and therapeutic target for ESCC.

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Wnt5a / planar cell polarity signaling pathway in urothelial carcinoma, a potential prognostic biomarker

Cited by 9 publications

References 34 publications

The Role of CTHRC1 in Regulation of Multiple Signaling and Tumor Progression and Metastasis

The Role of CTHRC1 in Regulation of Multiple Signaling and Tumor Progression and Metastasis

Leptin Is Associated with Poor Clinical Outcomes and Promotes Clear Cell Renal Cell Carcinoma Progression

<p><em>Let-7c-5p</em> Inhibits Cell Proliferation and Migration and Promotes Apoptosis via the CTHRC1/AKT/ERK Pathway in Esophageal Squamous Cell Carcinoma</p>

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