# WWC proteins as emerging biomarkers and therapeutic targets in cancer pathogenesis **Authors:** Shuge Wang, Junzhe Li, Xianhua Xu, Shijie Xu PMC · DOI: 10.3389/fcell.2026.1712319 · Frontiers in Cell and Developmental Biology · 2026-02-05 ## TL;DR This review explores how WWC proteins influence cancer development and could serve as targets for new treatments. ## Contribution The paper highlights the context-dependent roles of WWC1, WWC2, and WWC3 in cancer and their potential as therapeutic targets. ## Key findings - WWC2 consistently acts as a tumor suppressor across various cancers. - WWC1 and WWC3 show tissue-specific variability in their roles. - WWC proteins regulate key cancer pathways like Hippo and Wnt. ## Abstract WW and C2 domain-containing (WWC) proteins have emerged as pivotal regulators of cancer initiation, progression, and therapeutic resistance. This review synthesizes current evidence demonstrating that WWC1, WWC2, and WWC3 exert context-dependent effects across malignancies, with WWC2 consistently functioning as a tumor suppressor while WWC1 and WWC3 display tissue-specific variability. By integrating and regulating multiple signaling pathways, particularly Hippo and Wnt, WWC proteins function as molecular scaffolds that regulate proliferation, apoptosis, epithelial-mesenchymal transition, and metastasis. This review provides a comprehensive overview of the molecular characteristics, biological functions, and clinical implications of WWC proteins, highlighting their potential as prognostic biomarkers and therapeutic targets for precision oncology. ## Linked entities - **Genes:** WWC1 (WW and C2 domain containing 1) [NCBI Gene 23286], WWC2 (WW and C2 domain containing 2) [NCBI Gene 80014], WWC3 (WWC family member 3) [NCBI Gene 55841] - **Diseases:** cancer (MONDO:0004992) ## Full-text entities - **Genes:** AREG (amphiregulin) [NCBI Gene 374] {aka AR, AREGB, CRDGF, SDGF}, DDR1 (discoidin domain receptor tyrosine kinase 1) [NCBI Gene 780] {aka CAK, CD167, DDR, EDDR1, HGK2, MCK10}, DVL2 (dishevelled segment polarity protein 2) [NCBI Gene 1856], DLC1 (DLC1 Rho GTPase activating protein) [NCBI Gene 10395] {aka ARHGAP7, HP, STARD12, p122-RhoGAP}, ESR1 (estrogen receptor 1) [NCBI Gene 2099] {aka ER, ESR, ESRA, ESTRR, Era, NR3A1}, Wwc1 (WW, C2 and coiled-coil domain containing 1) [NCBI Gene 211652] {aka Kibra}, SAV1 (salvador family WW domain containing protein 1) [NCBI Gene 60485] {aka SAV, WW45, WWP4}, EGFR (epidermal growth factor receptor) [NCBI Gene 1956] {aka ERBB, ERBB1, ERRP, HER1, NISBD2, NNCIS}, GSK3B (glycogen synthase kinase 3 beta) [NCBI Gene 2932], BECN1 (beclin 1) [NCBI Gene 8678] {aka ATG6, VPS30, beclin1}, SLTM (SAFB like transcription modulator) [NCBI Gene 79811] {aka Met}, MIR215 (microRNA 215) [NCBI Gene 406997] {aka MIRN215, miRNA215, mir-215}, MEX3A (mex-3 RNA binding family member A) [NCBI Gene 92312] {aka MEX-3A, RKHD4, RNF162}, RASSF1 (Ras association domain family member 1) [NCBI Gene 11186] {aka 123F2, NORE2A, RASSF1A, RDA32, REH3P21}, MIR21 (microRNA 21) [NCBI Gene 406991] {aka MIRN21, hsa-mir-21, miR-21, miRNA21}, AMOT (angiomotin) [NCBI Gene 154796], WWTR1 (WW domain containing transcription regulator 1) [NCBI Gene 25937] {aka TAZ}, SNAI1 (snail family transcriptional repressor 1) [NCBI Gene 6615] {aka SLUGH2, SNA, SNAH, SNAIL, SNAIL1, dJ710H13.1}, SNAI2 (snail family transcriptional repressor 2) [NCBI Gene 6591] {aka SLUG, SLUGH, SLUGH1, SNAIL2, WS2D}, FRMD1 (FERM domain containing 1) [NCBI Gene 79981] {aka bA164L23.1}, WWC2 (WW and C2 domain containing 2) [NCBI Gene 80014] {aka BOMB}, MIR10B (microRNA 10b) [NCBI Gene 406903] {aka MIRN10B, hsa-mir-10b, miRNA10B, mir-10b}, CTNNB1 (catenin beta 1) [NCBI Gene 1499] {aka CTNNB, EVR7, MRD19, NEDSDV, armadillo}, CACUL1 (CDK2 associated cullin domain 1) [NCBI Gene 143384] {aka C10orf46, CAC1}, LINC00460 (long intergenic non-protein coding RNA 460) [NCBI Gene 728192], LATS2 (large tumor suppressor kinase 2) [NCBI Gene 26524] {aka KPM}, TAOK1 (TAO kinase 1) [NCBI Gene 57551] {aka DDIB, KFC-B, MAP3K16, MARKK, PSK-2, PSK2}, WWC1 (WW and C2 domain containing 1) [NCBI Gene 23286] {aka HBEBP3, HBEBP36, KIBRA, MEMRYQTL, PPP1R168}, SP1 (Sp1 transcription factor) [NCBI Gene 6667], IGHV3-69-1 (immunoglobulin heavy variable 3-69-1 (pseudogene)) [NCBI Gene 28402] {aka IGHV3-H, IGHV3H}, NF2 (NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor) [NCBI Gene 4771] {aka ACN, BANF, SCH, SWNV, merlin-1}, TP63 (tumor protein p63) [NCBI Gene 8626] {aka AIS, B(p51A), B(p51B), EEC3, KET, LMS}, WBP2 (WW domain binding protein 2) [NCBI Gene 23558] {aka DFNB107, GRAMD6, WBP-2}, YAP1 (Yes1 associated transcriptional regulator) [NCBI Gene 10413] {aka COB1, YAP, YAP-1, YAP2, YAP65, YKI}, Wwc2 (WW, C2 and coiled-coil domain containing 2) [NCBI Gene 52357] {aka 5330431C14Rik, D8Ertd594e}, ERG (ETS transcription factor ERG) [NCBI Gene 2078] {aka LMPHM14, erg-3, p55}, PICK1 (protein interacting with PRKCA 1) [NCBI Gene 9463] {aka PICK, PRKCABP}, PLEKHM2 (pleckstrin homology and RUN domain containing M2) [NCBI Gene 23207] {aka SKIP}, FUS (FUS RNA binding protein) [NCBI Gene 2521] {aka ALS6, ETM4, FUS1, HNRNPP2, POMP75, TLS}, EGF (epidermal growth factor) [NCBI Gene 1950] {aka HOMG4, URG}, RUNX1 (RUNX family transcription factor 1) [NCBI Gene 861] {aka AML1, AML1-EVI-1, AMLCR1, CBF2alpha, CBFA2, EVI-1}, RHOA (ras homolog family member A) [NCBI Gene 387] {aka ARH12, ARHA, EDFAOB, RHO12, RHOH12}, TXK (TXK tyrosine kinase) [NCBI Gene 7294] {aka BTKL, PSCTK5, PTK4, RLK, TKL}, ACTL6A (actin like 6A) [NCBI Gene 86] {aka ACTL6, ARPN-BETA, Arp4, BAF53A, INO80K, SMARCN1}, ERBB2 (erb-b2 receptor tyrosine kinase 2) [NCBI Gene 2064] {aka CD340, HER-2, HER-2/neu, HER2, MLN 19, MLN-19}, NUFIP2 (nuclear FMR1 interacting protein 2) [NCBI Gene 57532] {aka 182-FIP, 82-FIP, FIP-82, NUFP2, PIG1}, TCF7L2 (transcription factor 7 like 2) [NCBI Gene 6934] {aka TCF-4, TCF4}, GFER (growth factor, augmenter of liver regeneration) [NCBI Gene 2671] {aka ALR, ERV1, HERV1, HPO, HPO1, HPO2}, ETV6 (ETS variant transcription factor 6) [NCBI Gene 2120] {aka TEL, TEL/ABL, THC5}, CD38 (CD38 molecule) [NCBI Gene 952] {aka ADPRC 1, ADPRC1, cADPR1}, TAFAZZIN (tafazzin, phospholipid-lysophospholipid transacylase) [NCBI Gene 6901] {aka BTHS, CMD3A, EFE, EFE2, G4.5, LVNCX}, TCF4 (transcription factor 4) [NCBI Gene 6925] {aka CDG2T, E2-2, FCD2, FECD3, ITF-2, ITF2}, AR (androgen receptor) [NCBI Gene 367] {aka AIS, AR8, DHTR, HPCX3, HUMARA, HYSP1}, WWC3 (WWC family member 3) [NCBI Gene 55841] {aka BM042}, CSNK1E (casein kinase 1 epsilon) [NCBI Gene 1454] {aka CKIe, CKIepsilon, HCKIE}, PGR (progesterone receptor) [NCBI Gene 5241] {aka NR3C3, PR}, FRMPD1 (FERM and PDZ domain containing 1) [NCBI Gene 22844] {aka FRMD2}, PARD3 (par-3 family cell polarity regulator) [NCBI Gene 56288] {aka ASIP, Baz, PAR3, PAR3alpha, PARD-3, PARD3A}, DVL1P1 (dishevelled segment polarity protein 1 pseudogene 1) [NCBI Gene 8215] {aka DVL-22, DVL1L1}, BACH2 (BACH transcriptional regulator 2) [NCBI Gene 60468] {aka BTBD25, IMD60} - **Diseases:** HCC (MESH:D006528), ccRCC (MESH:D002292), MGUS (MESH:D008998), bladder cancer (MESH:D001749), brain malignancies (MESH:D001932), type 2 diabetes (MESH:D003924), breast cancer (MESH:D001943), triple-negative breast cancer (MESH:D064726), positive (MESH:D000377), acute lymphoblastic leukemia (MESH:D054198), metastasis (MESH:D009362), endometrial cancer (MESH:D016889), brain, kidney, breast, lung, liver, and gastrointestinal tract (MESH:D061325), urothelial carcinoma (MESH:D014523), CRC (MESH:D015179), neurological disorders (MESH:D009461), kidney cancer (MESH:D007680), hematologic malignancies (MESH:D019337), NSCLC (MESH:D002289), DPM (MESH:D000086002), LUAD (MESH:D000077192), GC (MESH:D013274), schwannomatosis (MESH:C536641), gastric carcinogenesis (MESH:D063646), iCCA (MESH:D018281), lung cancer (MESH:D008175), MM (MESH:D009101), Alzheimer's disease (MESH:D000544), cancer (MESH:D009369), schwannoma (MESH:D009442), esophageal squamous cell carcinoma (MESH:D000077277), osteosarcoma (MESH:D012516), inflammatory (MESH:D007249), upper tract urothelial carcinoma (MESH:D012141), prostate cancer (MESH:D011471), fibrosis (MESH:D005355), Gliomas (MESH:D005910), cervical cancer (MESH:D002583), pancreatic cancer (MESH:D010190), CLL (MESH:D015451) - **Chemicals:** 5-azacytidine (MESH:D001374), Ca2+ (-), regorafenib (MESH:C559147), sorafenib (MESH:D000077157), phospholipid (MESH:D010743), salt (MESH:D012492) - **Species:** Homo sapiens (human, species) [taxon 9606], Mus musculus (house mouse, species) [taxon 10090], Saccharomyces cerevisiae (baker's yeast, species) [taxon 4932] - **Mutations:** rs755813, rs147106204 ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12916667/full.md ## Figures 3 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12916667/full.md ## References 85 references — full list in the complete paper: https://tomesphere.com/paper/PMC12916667/full.md --- Source: https://tomesphere.com/paper/PMC12916667