RSPO2 As Wnt Signaling Enabler: Important Roles in Cancer Development and Therapeutic Opportunities

Overview

Journal Genes Dis

Date 2023 Sep 11

PMID 37692504

Authors

Ankit Srivastava

Deeksha Rikhari

Sameer Srivastava

Affiliations

Soon will be listed here.

Abstract

R-spondins are secretory proteins localized in the endoplasmic reticulum and Golgi bodies and are processed through the secretory pathway. Among the R-spondin family, RSPO2 has emanated as a novel regulator of Wnt signaling, which has now been acknowledged in numerous and studies. Cancer is an abnormal growth of cells that proliferates and spreads uncontrollably due to the accumulation of genetic and epigenetic factors that constitutively activate Wnt signaling in various types of cancer. Colorectal cancer (CRC) begins when cells in the colon and rectum follow an indefinite pattern of division due to aberrant Wnt activation as one of the key hallmarks. Decades-long progress in research on R-spondins has demonstrated their oncogenic function in distinct cancer types, particularly CRC. As a critical regulator of the Wnt pathway, it modulates several phenotypes of cells, such as cell proliferation, invasion, migration, and cancer stem cell properties. Recently, RSPO mutations, gene rearrangements, fusions, copy number alterations, and altered gene expression have also been identified in a variety of cancers, including CRC. In this review, we addressed the recent updates regarding the recurrently altered R-spondins with special emphasis on the RSPO2 gene and its involvement in potentiating Wnt signaling in CRC. In addition to the compelling physiological and biological roles in cellular fate and regulation, we propose that RSPO2 would be valuable as a potential biomarker for prognostic, diagnostic, and therapeutic use in CRC.

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References

Klein F, Feldhahn N, Herzog S, Sprangers M, Mooster J, Jumaa H . BCR-ABL1 induces aberrant splicing of IKAROS and lineage infidelity in pre-B lymphoblastic leukemia cells. Oncogene. 2005; 25(7):1118-24. DOI: 10.1038/sj.onc.1209133. View

Lee H, Seidl C, Sun R, Glinka A, Niehrs C . R-spondins are BMP receptor antagonists in Xenopus early embryonic development. Nat Commun. 2020; 11(1):5570. PMC: 7642414. DOI: 10.1038/s41467-020-19373-w. View

Theodorou V, Kimm M, Boer M, Wessels L, Theelen W, Jonkers J . MMTV insertional mutagenesis identifies genes, gene families and pathways involved in mammary cancer. Nat Genet. 2007; 39(6):759-69. DOI: 10.1038/ng2034. View

Ruffner H, Sprunger J, Charlat O, Leighton-Davies J, Grosshans B, Salathe A . R-Spondin potentiates Wnt/β-catenin signaling through orphan receptors LGR4 and LGR5. PLoS One. 2012; 7(7):e40976. PMC: 3397969. DOI: 10.1371/journal.pone.0040976. View

Seitz C, van Steensel M, Frank J, Senderek J, Zerres K, Hamm H . The Wnt signalling ligand RSPO4, causing inherited anonychia, is not mutated in a patient with congenital nail hypoplasia/aplasia with underlying skeletal defects. Br J Dermatol. 2007; 157(4):801-2. DOI: 10.1111/j.1365-2133.2007.08059.x. View

Ilmer M, Boiles A, Regel I, Yokoi K, Michalski C, Wistuba I . RSPO2 Enhances Canonical Wnt Signaling to Confer Stemness-Associated Traits to Susceptible Pancreatic Cancer Cells. Cancer Res. 2015; 75(9):1883-96. DOI: 10.1158/0008-5472.CAN-14-1327. View

Moad H, Pioszak A . Reconstitution of R-spondin:LGR4:ZNRF3 adult stem cell growth factor signaling complexes with recombinant proteins produced in Escherichia coli. Biochemistry. 2013; 52(41):7295-304. PMC: 3836688. DOI: 10.1021/bi401090h. View

Coussy F, Lallemand F, Vacher S, Schnitzler A, Chemlali W, Caly M . Clinical value of R-spondins in triple-negative and metaplastic breast cancers. Br J Cancer. 2017; 116(12):1595-1603. PMC: 5518860. DOI: 10.1038/bjc.2017.131. View

Koo B, Spit M, Jordens I, Low T, Stange D, van de Wetering M . Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature. 2012; 488(7413):665-9. DOI: 10.1038/nature11308. View

10.

Lepourcelet M, Chen Y, France D, Wang H, Crews P, Petersen F . Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex. Cancer Cell. 2004; 5(1):91-102. DOI: 10.1016/s1535-6108(03)00334-9. View

11.

Han X, Jin Y, Seto M, Yoon J . A WNT/beta-catenin signaling activator, R-spondin, plays positive regulatory roles during skeletal myogenesis. J Biol Chem. 2011; 286(12):10649-59. PMC: 3060516. DOI: 10.1074/jbc.M110.169391. View

12.

Lee S, Kim O, Lee S, Kim S . IWR-1 inhibits epithelial-mesenchymal transition of colorectal cancer cells through suppressing Wnt/β-catenin signaling as well as survivin expression. Oncotarget. 2015; 6(29):27146-59. PMC: 4694979. DOI: 10.18632/oncotarget.4354. View

13.

Bergmann C, Senderek J, Anhuf D, Thiel C, Ekici A, Poblete-Gutierrez P . Mutations in the gene encoding the Wnt-signaling component R-spondin 4 (RSPO4) cause autosomal recessive anonychia. Am J Hum Genet. 2006; 79(6):1105-9. PMC: 1698700. DOI: 10.1086/509789. View

14.

Zebisch M, Xu Y, Krastev C, MacDonald B, Chen M, Gilbert R . Structural and molecular basis of ZNRF3/RNF43 transmembrane ubiquitin ligase inhibition by the Wnt agonist R-spondin. Nat Commun. 2013; 4:2787. PMC: 3905715. DOI: 10.1038/ncomms3787. View

15.

Singh M, Rai S, Singh N, Srivastava S . Transcriptomic landscape of early age onset of colorectal cancer identifies novel genes and pathways in Indian CRC patients. Sci Rep. 2021; 11(1):11765. PMC: 8175339. DOI: 10.1038/s41598-021-91154-x. View

16.

Li S, Yen T, Endo Y, Klauzinska M, Baljinnyam B, Macher B . Loss-of-function point mutations and two-furin domain derivatives provide insights about R-spondin2 structure and function. Cell Signal. 2009; 21(6):916-25. PMC: 2813491. DOI: 10.1016/j.cellsig.2009.02.001. View

17.

Longerich T, Endris V, Neumann O, Rempel E, Kirchner M, Abadi Z . gene rearrangement: a powerful driver of β-catenin activation in liver tumours. Gut. 2019; 68(7):1287-1296. DOI: 10.1136/gutjnl-2018-317632. View

18.

. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001; 69(3):89-95. DOI: 10.1067/mcp.2001.113989. View

19.

Seshagiri S, Stawiski E, Durinck S, Modrusan Z, Storm E, Conboy C . Recurrent R-spondin fusions in colon cancer. Nature. 2012; 488(7413):660-4. PMC: 3690621. DOI: 10.1038/nature11282. View

20.

Sato T, Vries R, Snippert H, van de Wetering M, Barker N, Stange D . Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009; 459(7244):262-5. DOI: 10.1038/nature07935. View