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This review focuses on non-canonical Wnt signaling, including Wnt/PCP and Wnt/Ca2+ pathways, and highlights Wnt-5a as a well-studied ligand. The role of non-canonical Wnt and Wnt-5a in cancer is mosaic, capable of tumor-promoting or tumor-suppressing effects, with controversy in colorectal cancer.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/colorectal-cancer-and-the-enigma-surrounding-non-canonical-wnt-signaling/354655/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/colorectal-cancer-and-the-enigma-surrounding-non-canonical-wnt-signaling/354655.png","ImageObject",300,407,{"name":92,"@type":93},"mieayamfan","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-23","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":14},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why is non-canonical Wnt signaling considered relevant to colorectal cancer?","Question",{"text":112,"@type":113},"Although canonical Wnt/β-catenin signaling is critical for tumorigenesis, a meaningful subset of colorectal cancer patients lack canonical pathway mutations, suggesting additional, Wnt-independent signaling routes such as non-canonical Wnt signaling.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What non-canonical Wnt pathways are discussed in the review?",{"text":117,"@type":113},"The review discusses non-canonical Wnt signaling pathways including Wnt/PCP and Wnt/Ca2+ pathways, emphasizing their potential involvement in cancer progression.",{"name":119,"@type":110,"acceptedAnswer":120},"How is the role of Wnt-5a in cancer characterized?",{"text":121,"@type":113},"Wnt-5a–initiated non-canonical signaling is described as mosaic, meaning it may promote or suppress tumors depending on context, and colorectal cancer results are reported as highly controversial.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},354655,1790177285,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":14,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},962090893677,"https://ap-avatar.wpscdn.com/davatar_3d24733baf745e90a7e4bdd5f77d97b2","Review  \nColorectal Cancer and the Enigma Surrounding Non-Canonical Wnt Signaling  \nKatsuhiro Kita   \nAcademic Editors: Alain P. Gobert, Patrick Okolo and Chengu Niu  \nReceived: 1 July 2026  \nRevised: 9 August 2026  \nAccepted: 10 August 2026  \nPublished: 14 August 2026  \nCopyright: © 2026 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.  \nDepartment of Biology, St. Francis College, Brooklyn, NY 11201, USA; [kkita@sfc.edu](kkita@sfc.edu)  \nSimple Summary  \nColon cancer is still the second leading cause of death worldwide, as well as in the United States. Although the majority of colon cancer cases may have mutations in key molecules of one signaling pathway called the Wnt/β-catenin pathway, there is still a certain percentage of patients suffering from colon cancer through a different signaling pathway. Wnt family consists of many molecules and is also transmitted via the non-β-catenin pathway (noncanonical Wnt signaling) . In this review, I would like to shed light on the unclear role of non-canonical Wnt signaling in colon cancer, with a particular focus on one of the Wnt, Wnt-5a.  \nAbstract  \nSince the discovery of truncated mutations of adenomatous polyposis coli proteins in familial adenoma patients in 1991, the mechanism of cytosolic β-catenin regulation has been intensively studied, and now it is very well known that the central role of the canonical Wnt/β-catenin is in colorectal cancer. However, Wnt signaling is very complicated because of the presence of almost 20 Wnt ligand genes, six Frizzled seven-transmembrane receptors, and three LRP co-receptors. In addition, research in the past two decades illuminated the existence of the other Wnt signaling—non-canonical Wnt signaling (Wnt/PCP and Wnt/Ca2+ pathways), and an increasing number of studies have shown the potential role of non-canonical Wnt signaling in cancer recently. One of the well-studied Wnt ligands in non-canonical Wnt signaling is Wnt-5a. However, the role of Wnt-5a and non-canonical pathways in cancer is mosaic—i.e., it may involve tumor-promoting or suppressing pathways. In certain cancers, non-canonical Wnt signaling may mainly act asa tumor promoter, yet the results are very controversial in colorectal cancer. Elucidating the role of non-canonical Wnt signaling in colorectal cancer may be very important to further reduce the risk of colorectal cancer, especially in patients who do not carry truncated mutations of adenomatous polyposis coli. In this review, I would like to mainly discuss the apparent controversy surrounding non-canonical Wnt signaling in colorectal cancer, and I would like to point out a few potential reasons contributing to the mysterious roles of Wnt5a-initiated non-canonical signaling in colorectal cancer.  \nKeywords: non-canonical Wnt; colorectal cancer; Wnt-5a; ROR2; hypoxia; cancerassociated fibroblasts  \n1. Introduction  \nDespite a more than 50% decrease in the overall mortality of colorectal cancer (CRC) from 1970 to 2020, CRC still remains the second leading cause of cancer-associated death in  \nthe United States and the world [1] . In CRC, the role of the Wnt/β-catenin signaling pathway has been well-acknowledged as one of the critical pathways involved in tumorigenesis, and thus, has been well-investigated. In canonical Wnt/β-catenin signaling, β-catenin is destroyed by ubiquitin-mediated proteolysis [2] . Regarding CRC, sporadic adenomatous polyposis coli (APC) truncated mutations occur in more than 80% of patients [3] and thus prevent the degradation of β-catenin, leading to the accumulation of cytosolic β-catenin.  \nThe first series of studies connecting Wnt signaling to cancer dates back to the early 1990s, performed by Dr. Harold Varmus’ lab and colleagues [4] . Those studies demonstrated that Wnt1 can promote tumorigenesis in some way. Around the same time, mutations of one of the key r","cbCaioHl7Ohy6MAQ","https://ap.wps.com/l/cbCaioHl7Ohy6MAQ","pdf",1266773,21,"English","# 1. Introduction","[{\"question\":\"Why is non-canonical Wnt signaling considered relevant to colorectal cancer?\",\"answer\":\"Although canonical Wnt/β-catenin signaling is critical for tumorigenesis, a meaningful subset of colorectal cancer patients lack canonical pathway mutations, suggesting additional, Wnt-independent signaling routes such as non-canonical Wnt signaling.\"},{\"question\":\"What non-canonical Wnt pathways are discussed in the review?\",\"answer\":\"The review discusses non-canonical Wnt signaling pathways including Wnt/PCP and Wnt/Ca2+ pathways, emphasizing their potential involvement in cancer progression.\"},{\"question\":\"How is the role of Wnt-5a in cancer characterized?\",\"answer\":\"Wnt-5a–initiated non-canonical signaling is described as mosaic, meaning it may promote or suppress tumors depending on context, and colorectal cancer results are reported as highly controversial.\"}]","Colorectal Cancer and the Enigma Surrounding Non-Canonical Wnt Signaling | PDF",1790112784,53]