Dysregulation of WNT5A/ROR2 Signaling Characterizes the Progression of Barrett-Associated Esophageal Adenocarcinoma

Lyros, Orestis; Nie, Lei; Moore, Tami; Medda, Rituparna; Otterson, Mary F.; Behmaram, Behnaz; Mackinnon, Alexander C.; Gockel, Ines; Shaker, Reza; Rafiee, Parvaneh

doi:10.1158/1541-7786.mcr-15-0484

Cited by 13 publications

(6 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ROR2 has been reported to have different effects on cell proliferation, growth, migration, and invasion across different tumors. Many studies have shown that ROR2 promotes cell proliferation and migration in renal cell carcinoma ( 15 ), esophageal cancer cells WT33 ( 16 ), leiomyosarcoma, and gastrointestinal stromal tumor ( 35 ). Lara et al ( 14 ) found that, along with overexpression of ROR2, proliferation and growth of colon cancer cells in vivo and in vitro were weakened.…”

Section: Discussionmentioning

confidence: 99%

“…ROR2 plays different roles in the malignant behavior of tumors. For instance, ROR2 accelerates tumor proliferation and migration in renal and esophageal cancers, promote migration rather than proliferation in some breast and ovarian cancer cells, and inhibit both proliferation and migration in certain colorectal cancer cells related to promoter hypermethylation (8,9,(14)(15)(16). However, the role of ROR2 in gastric cancers has not been extensively studied.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Role of ROR2 in promoting gastric cancer metastasis by enhancing c-JUN-mediated MMP3 transcription

Ge¹,

Lin²,

Wu³

et al. 2022

Ann Transl Med

View full text Add to dashboard Cite

Background: Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a transmembrane receptor that has a complex role in cancer, acting either to promote or inhibit tumor progression in different tumor types.The effect of ROR2 on gastric cancer is unclear.Methods: Immunohistochemistry was used to investigate the role of ROR2 in the prognosis of gastric cancer. Transwell assay and a BALB/c nude mice pulmonary metastasis model were used to ascertain the role of ROR2 in promoting metastasis in vitro and in vivo. A protein expression array, chromatin immunoprecipitation (ChIP) assay, and luciferase reporter assay were employed to search for the target genes of ROR2.Results: ROR2 was found to be upregulated in gastric cancer tissues, which was correlated with poor disease-free survival (DFS) and overall survival (OS) in gastric cancer patients. Moreover, ROR2 promoted gastric cancer cell migratory and invasive behaviors in vitro and metastasis in vivo. Further research showed that ROR2 promoted gastric cancer metastasis via upregulation of matrix metalloproteinase 3 (MMP3).Analyses of clinical data indicated that high expression of ROR2 was correlated with a high expression of MMP3. Further study showed that ROR2 activated c-JUN by translocating phosphorylated JNK1/2 into the nucleus, and c-JUN interacted directly with the MMP3 promoter, leading to enhanced MMP3 transcription.Conclusions: We report for the first time that ROR2 is upregulated in gastric cancer, promotes metastasis, and is associated with poor prognosis in gastric cancer. The findings suggest that ROR2 may be a promising prognostic predictor for gastric cancer. Silencing the JNK1/2-c-JUN pathway, thereby inhibiting MMP3 expression, may serve as a promising strategy to inhibit gastric cancer progression.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of ROR2 in promoting gastric cancer metastasis by enhancing c-JUN-mediated MMP3 transcription

Ge¹,

Lin²,

Wu³

et al. 2022

Ann Transl Med

View full text Add to dashboard Cite

show abstract

“…On the other hand, Huang and colleagues recently supported that high ROR2expression is associated with poor prognosis without, however, to evaluate WNT5A-expression patterns or other downstream molecules of the ROR2 receptor in their cohort [25] . Regarding other malignancies, several reports have attempted to investigate the prognostic values of ROR2 and WNT5A in combination, supporting the viewpoint that double positive cancers (ROR2+/WNT5A+) might have signi cantly worse survival than those with double negative cancers (ROR2-/WNT5A-) [29][30][31][32][33][34] , while other studies suggest independent roles for WNT5A as tumor-suppressor and for ROR2-receptor as mediator of WNT5Aindependent tumor-promotion [35,36,10] . This variety in WNT5A and ROR2 molecular functions in regard to tumor progression, surely re ects the differences in the receptor-ligand context or cell context of cancer cells even in PDAC and can in part explain the lack of signi cance, even in the subgroup analysis.…”

Section: Discussionmentioning

confidence: 94%

The WNT5A/ROR2 signaling pathway in pancreatic ductal adenocarcinoma (PDAC)

Remtisch

Wiltberger²,

Schierle³

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Background WNT5A/ROR2 signaling pathway has been shown to be involved in many human cancers. Its role in pancreatic ductal adenocarcinoma (PDAC) has not been clarified yet. The aim of this study was to determine the prognostic value of WNT5A-expression in conjunction with the ROR2-expression in the same tumor tissues of PDAC patients. Methods We retrospectively analyzed the expression of WNT5A and ROR2 in 117 paraffin-embedded PDAC specimens following surgical pancreatic resection by immunohistochemistry. The prognostic value of WNT5A and ROR2 was assessed using Kaplan-Meier survival curves and multivariate COX regression-models. Results High ROR2-expression was detected in 65.8% (77/117) of PDAC-tumors, in 28.2% (33/117) in tumor-stroma, and in 71.1% (65/90) of normal pancreatic tissue. High WNT5A-expression was found in 76.9% (90/117) of tumors, in 59.0% (69/117) of tumor-stroma, and in 83.0% (73/88) of normal pancreatic tissue. Spearman's correlation co-efficiency demonstrated weak association between ROR2- and WNT5A-expression in tumor (r = 0.184; p = 0.047), and no association in stroma (r = 0.036; p = 0.699). Multivariate analysis showed that regional lymph node invasion and differentiation were independent prognostic factors of survival, while ROR2- and WNT5A-expression not. Conclusions Variable expression patterns for ROR2 and WNT5A were demonstrated in PDAC and normal pancreatic tissues suggesting a role for WNT5A/ROR2 signalling pathway, not only in PDAC but also in the normal pancreatic tissue during inflammation. The lack of prognostic significance for ROR2- and WNT5A-expression in our cohort, either alone or in subgroup analysis, signifies the complexity of their role in PDAC, which is highly dependent on the different molecular receptor-ligand tissue contexts.

show abstract

“…Moreover, wingless-type protein 5a (Wnt5a) can add FAO and OXPHOS by downregulating PPAR γ [ 177 ]. As indicated by the experimental studies of Lyros et al, abnormal regulation of the Wnt5a/receptor tyrosine kinase-like orphan receptor 2 (ROR2) signaling pathway could facilitate the development of Barrett-associated esophageal adenocarcinoma [ 178 ]. As reported by Wu et al, Wnt5a can improve the invasive ability of ESCC cells via a wide variety of signaling pathways [ 179 ].…”

Section: Introduction To Esophageal Cancermentioning

confidence: 99%

Targeting Strategies for Aberrant Lipid Metabolism Reprogramming and the Immune Microenvironment in Esophageal Cancer: A Review

Cui

Cao

et al. 2022

Journal of Oncology

View full text Add to dashboard Cite

Esophageal cancer is of high importance to occurrence, development, and treatment resistance. As evidenced by recent studies, pathways (e.g., Wnt/β-catenin, AMPK, and Hippo) are critical to the proliferation, differentiation, and self-renewal of esophageal cancer. In addition, the above pathways play a certain role in regulating esophageal cancer and act as potential therapeutic targets. Over the past few years, the function of lipid metabolism in controlling tumor cells and immune cells has aroused extensive attention. It has been reported that there are intricate interactions between lipid metabolism reprogramming between immune and esophageal cancer cells, whereas molecular mechanisms should be studied in depth. Immune cells have been commonly recognized as a vital player in the esophageal cancer microenvironment, having complex crosstalk with cancer cells. It is increasingly evidenced that the function of immune cells in the tumor microenvironment (TME) is significantly correlated with abnormal lipid metabolism. In this review, the latest findings in lipid metabolism reprogramming in TME are summarized, and the above findings are linked to esophageal cancer progression. Aberrant lipid metabolism and associated signaling pathways are likely to serve as a novel strategy to treat esophageal cancer through lipid metabolism reprogramming.

show abstract

Dysregulation of WNT5A/ROR2 Signaling Characterizes the Progression of Barrett-Associated Esophageal Adenocarcinoma

Cited by 13 publications

References 39 publications

Role of ROR2 in promoting gastric cancer metastasis by enhancing c-JUN-mediated MMP3 transcription

Role of ROR2 in promoting gastric cancer metastasis by enhancing c-JUN-mediated MMP3 transcription

The WNT5A/ROR2 signaling pathway in pancreatic ductal adenocarcinoma (PDAC)

Targeting Strategies for Aberrant Lipid Metabolism Reprogramming and the Immune Microenvironment in Esophageal Cancer: A Review

Contact Info

Product

Resources

About