Ectopic repression of receptor tyrosine kinase–like orphan receptor 2 inhibits malignant transformation of ovarian cancer cells by reversing epithelial–mesenchymal transition

Xu, Ying; Ma, Yonggang; Pang, Yingxin; Zhao, Zhe; Lu, Jingjing; Mao, Hongluan; Liu, Peishu

doi:10.1177/1010428317701627

Cited by 10 publications

(13 citation statements)

References 41 publications

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“…In vitro , FZD7 drove the aggressiveness of this particular HGSC subtype by regulating cell proliferation, cell cycle progression, maintenance of the mesenchymal phenotype, and cell migration capability via casein kinase 1ε (CK1ε)-mediated WNT/PCP pathway 57. This and other studies 18, 20-22, 58 in the context of our findings point toward the crucial role of WNT5A/ROR/DVL/CK1 axis in the progression of HGSC.…”

Section: Discussionsupporting

confidence: 73%

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WNT signaling inducing activity in ascites predicts poor outcome in ovarian cancer

Kotrbová¹,

Ovesná²,

Gybeľ³

et al. 2020

Theranostics

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High grade serous carcinoma of the ovary, fallopian tube, and peritoneum (HGSC) is the deadliest gynecological disease which results in a five-year survival rate of 30% or less. HGSC is characterized by the early and rapid development of metastases accompanied by a high frequency of ascites i.e. the pathological accumulation of fluid in peritoneum. Ascites constitute a complex tumor microenvironment and contribute to disease progression by largely unknown mechanisms.Methods: Malignant ascites obtained from HGSC patients who had undergone cytoreductive surgery were tested for their ability to induce WNT signaling in the Kuramochi cell line, a novel and clinically relevant in vitro model of HGSC. Next, cancer spheroids (the main form of metastatic cancer cells in ascites) were evaluated with respect to WNT signaling. Kuramochi cells were used to determine the role of individual WNT signaling branches in the adoption of metastatic stem cell-like behavior by HGSC cells. Furthermore, we analyzed genomic and transcriptomic data on WNT/Planar Cell Polarity (PCP) components retrieved from public cancer databases and corroborated with primary patient samples and validated antibodies on the protein level.Results: We have shown that ascites are capable of inducing WNT signaling in primary HGSC cells and HGSC cell line, Kuramochi. Importantly, patients whose ascites cannot activate WNT pathway present with less aggressive disease and a considerably better outcome including overall survival (OS). Functionally, the activation of non-canonical WNT/PCP signaling by WNT5A (and not canonical WNT/β-catenin signaling by WNT3A) promoted the metastatic stem-cell (metSC) like behavior (i.e. self-renewal, migration, and invasion) of HGSC cells. The pharmacological inhibition of casein kinase 1 (CK1) as well as genetic ablation (dishevelled 3 knock out) of the pathway blocked the WNT5A-induced effect. Additionally, WNT/PCP pathway components were differentially expressed between healthy and tumor tissue as well as between the primary tumor and metastases. Additionally, ascites which activated WNT/PCP signaling contained the typical WNT/PCP ligand WNT5A and interestingly, patients with high levels of WNT5A protein in their ascites exhibited poor progression-free survival (PFS) and OS in comparison to patients with low or undetectable ascitic WNT5A. Together, our results suggest the existence of a positive feedback loop between tumor cells producing WNT ligands and ascites that distribute WNT activity to cancer cells in the peritoneum, in order to promote their pro-metastatic features and drive HGSC progression.Conclusions: Our results highlight the role of WNT/PCP signaling in ovarian cancerogenesis, indicate a possible therapeutic potential of CK1 inhibitors for HGSC, and strongly suggest that the detection of WNT pathway inducing activity ascites (or WNT5A levels in ascites as a surrogate marker) could be a novel prognostic tool for HGSC patients.

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Section: Discussionsupporting

confidence: 73%

“…1A). Unfortunately, earlier studies focused primarily on the functional analysis of WNT signaling in OC using cell lines which may not be accurate, at least when compared to the molecular profile of HGSC 18-22. Therefore, we have performed our analyses with Kuramochi 23, the best scoring cell line with respect to HGSC molecular signature 17.…”

Section: Resultsmentioning

confidence: 99%

WNT signaling inducing activity in ascites predicts poor outcome in ovarian cancer

Kotrbová¹,

Ovesná²,

Gybeľ³

et al. 2020

Theranostics

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“…First reports about a pro-invasive function of ROR2 stem from studies on HeLa cells showing that WNT5A-ROR2 mediated polarized cell migration in this cell line [ 115 ]. This has since been confirmed in several solid tumor entities in which knockdown of ROR2 resulted in decreased migration and/or invasion, e.g., in mesothelioma [ 57 ], melanoma [ 79 ], renal cancer [ 89 ], breast cancer [ 114 ], ovarian cancer [ 59 , 99 , 116 , 117 ], prostate cancer [ 118 ], leiomyosarcoma, gastrointestinal stroma tumors [ 62 ], and osteosarcoma [ 61 ]. Taken together, the data imply that both ROR1 and ROR2 are associated with highly malignant cancer cell phenotypes characterized by high motility and aggressiveness.…”

Section: The Function Of Ror1/2 In Cancermentioning

confidence: 97%

“…Further in vitro studies have indeed confirmed higher expression of typical epithelial factors (e.g., CK19, CDH1) and lower expression of mesenchymal factors (e.g., SNAI2, ZEB1, VIM) after ROR1 or ROR2 knockdown in cancer cells. This is indicative of a role for both co-receptors in fostering EMT [ 42 , 56 , 80 , 111 , 113 , 117 ]. One explanation why the RORs are so closely associated with the EMT program is that their expression has been revealed to be under the control of key EMT-inducing transcription factors.…”

Section: The Function Of Ror1/2 In Cancermentioning

confidence: 99%

The WNT/ROR Pathway in Cancer: From Signaling to Therapeutic Intervention

Menck

Heinrichs

Baden

et al. 2021

Cells

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The WNT pathway is one of the major signaling cascades frequently deregulated in human cancer. While research had initially focused on signal transduction centered on β-catenin as a key effector activating a pro-tumorigenic transcriptional response, nowadays it is known that WNT ligands can also induce a multitude of β-catenin-independent cellular pathways. Traditionally, these comprise WNT/planar cell polarity (PCP) and WNT/Ca2+ signaling. In addition, signaling via the receptor tyrosine kinase-like orphan receptors (RORs) has gained increasing attention in cancer research due to their overexpression in a multitude of tumor entities. Active WNT/ROR signaling has been linked to processes driving tumor development and progression, such as cell proliferation, survival, invasion, or therapy resistance. In adult tissue, the RORs are largely absent, which has spiked the interest in them for targeted cancer therapy. Promising results in preclinical and initial clinical studies are beginning to unravel the great potential of such treatment approaches. In this review, we summarize seminal findings on the structure and expression of the RORs in cancer, their downstream signaling, and its output in regard to tumor cell function. Furthermore, we present the current clinical anti-ROR treatment strategies and discuss the state-of-the-art, as well as the challenges of the different approaches.

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“…23 Accumulating evidence further demonstrates that Ror2 is expressed highly in various types of cancer cells, and plays critical roles in regulating proliferation as well as migration and invasion of these cancer cells. [24][25][26][27] In cells stimulated with growth factors or cells harboring mutations in tumor suppressor genes like p53, retinoblastoma protein (Rb) is heavily phosphorylated by activated cyclin-dependent kinases (CDKs), leading to activation of E2F transcription factors to promote the cell cycle progression from G1 to S phase. [28][29][30][31][32][33] It has been shown that the suppressed expression of Ror2 results in reduced G1/S phase transition in astrocytes and cancer cells.…”

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confidence: 99%

E2F1‐Ror2 signaling mediates coordinated transcriptional regulation to promote G1/S phase transition in bFGF‐stimulated NIH/3T3 fibroblasts

2020

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Ror2 signaling has been shown to regulate the cell cycle progression in normal and cancer cells. However, the molecular mechanism of the cell cycle progression upon activation of Ror2 signaling still remains unknown. Here, we found that the expression levels of Ror2 in G1‐arrested NIH/3T3 fibroblasts are low and are rapidly increased following the cell cycle progression induced by basic fibroblast growth factor (bFGF) stimulation. By expressing wild‐type or a dominant negative mutant of E2F1, we show that E2F1 mediates bFGF‐induced expression of Ror2, and that E2F1 binds to the promoter of the Ror2 gene to activate its expression. We also found that G1/S phase transition of bFGF‐stimulated NIH/3T3 cells is delayed by the suppressed expression of Ror2. RNA‐seq analysis revealed that the suppressed expression of Ror2 results in the decreased expression of various E2F target genes concomitantly with increased expression of Forkhead box O (FoxO) target genes, including p21Cip1, and p27Kip1. Moreover, the inhibitory effect of Ror2 knockdown on the cell cycle progression can be restored by suppressed expression of p21Cip1, p27Kip1,or FoxO3a. Collectively, these findings indicate that E2F1‐Ror2 signaling mediates the transcriptional activation and inhibition of E2F1‐driven and FoxO3a‐driven cell cycle‐regulated genes, respectively, thereby promoting G1/S phase transition of bFGF‐stimulated NIH/3T3 cells.

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Ectopic repression of receptor tyrosine kinase–like orphan receptor 2 inhibits malignant transformation of ovarian cancer cells by reversing epithelial–mesenchymal transition

Cited by 10 publications

References 41 publications

WNT signaling inducing activity in ascites predicts poor outcome in ovarian cancer

WNT signaling inducing activity in ascites predicts poor outcome in ovarian cancer

The WNT/ROR Pathway in Cancer: From Signaling to Therapeutic Intervention

E2F1‐Ror2 signaling mediates coordinated transcriptional regulation to promote G1/S phase transition in bFGF‐stimulated NIH/3T3 fibroblasts

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