New Advances in Classical Wnt/β-Catenin Signaling in Cancer

A B S T R A C T

Wnt/β-catenin-mediated signaling is a key pathway regulating tissue growth and development and tumorigenesis. This signaling pathway has received much attention in recent years. In addition to participating in healthy tissue and organ development, inappropriate activation of this pathway can cause a variety of tumors and other pathologies. It also plays a critical role in many processes such as proliferation, differentiation, apoptosis, migration, invasion, epithelial-mesenchymal transition and dry maintenance of human tumor cells. This review introduces the underlying mechanism of Wnt signaling pathway and highlights the most recent research progresses on the relationship between Wnt signaling pathway and tumor. Furthermore, the intrinsic link of Wnt signaling pathway to cancer stem cells is also discussed, aiming to curb the malignant progression of tumors from the root cause. Finally, possible clinical strategies harnessing the classical Wnt signaling pathway as a therapeutic target are summarized.

Keywords

Wnt/β-catenin signaling, tumor, cancer stem cell, target, therapeutic strategy

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Akhlaq Ahmad Ailin Tao Mushtaq Ahmed Nadia Mushtaq Ayesha Ali Khan Qing-Xin Li Muhammad Wasim Jan Khan

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References

1. T Zhan, N Rindtorff, M Boutros (2017) Wnt signaling in cancer. Oncogene 36:1461-1473. [Crossref]
2. Maryam Majidinia, Javad Aghazadeh, Rana Jahanban Esfahlani, Bahman Yousefi (2018) The roles of Wnt/β-catenin pathway in tissue development and regenerative medicine. J Cell Physiol 233: 5598-5612. [Crossref]
3. Bojun Wang, Tian Tian, Karl Henning Kalland, Xisong Ke, Yi Qu (2018) Targeting Wnt/β-Catenin Signaling for Cancer Immunotherapy. Trends Pharmacol Sci 39: 648-658. [Crossref]
4. Hans Clevers, Roel Nusse (2012) Wnt/β-catenin signaling and disease. Cell 149: 1192-1205. [Crossref]
5. Carla Bänziger, Davide Soldini, Corina Schütt, Peder Zipperlen, George Hausmann et al. (2006) Wntless, a conserved membrane protein dedicated to the secretion of Wnt proteins from signaling cells. Cell 125: 509-522. [Crossref]
6. Roel Nusse, Hans Clevers (2017) Wnt/β-Catenin Signaling, Disease,and Emerging Therapeutic Modalities. Cell 169: 985-999. [Crossref]
7. Ken M Cadigan, Marian L Waterman (2012) TCF/LEFs and Wnt signaling in the nucleus. Cold Spring Harb Perspect Biol 4: a007906. [Crossref]
8. Lukas E Dow, Kevin P O'Rourke, Janelle Simon, Darjus F Tschaharganeh, Johan H van Es et al. (2015) Apc Restoration Promotes Cellular Differentiation and Reestablishes Crypt Homeostasis in Colorectal Cancer. Cell 161: 1539-1552. [Crossref]
9. Luca Azzolin, Tito Panciera, Sandra Soligo, Elena Enzo, Silvio Bicciato et al. (2014) YAP/TAZ Incorporation in the b-Catenin Destruction Complex Orchestrates the Wnt Response. Cell 158: 157-170. [Crossref]
10. Wim de Lau, Weng Chuan Peng, Piet Gros, Hans Clevers (2014) The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength. Genes Dev 28: 305-316. [Crossref]
11. Herb Brody (2015) Colorectal cancer. Nature 521: S1. [Crossref]
12. Cancer Genome Atlas Network (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487: 330-337. [Crossref]
13. Randall W Burt, Mark F Leppert, Martha L Slattery, Wade S Samowitz, Lisa N Spirio et al. (2004) Genetic testing and phenotype in a large kindred with attenuated familial adenomatous polyposis. Gastroenterology 127: 444-451. [Crossref]
14. Hwa Jin Kim, Sue Jin Moon, Seok Hyung Kim, Kyu Heo, Jeong Hoon Kim et al. (2018) DBC1 regulates Wnt/β-catenin-mediated expression of MACC1, a key regulator of cancer progression, in colon cancer. Cell Death Dis 9: 831. [Crossref]
15. Qingding Wang, Yuning Zhou, Piotr Rychahou, Jennifer W Harris, Yekaterina Y Zaytseva et al. (2018) Deptor is a novel target of Wnt/ -catenin/c-Myc and contributes to colorectal cancer cell growth. Cancer Res 78: 3163-3175. [Crossref]
16. Paulo Rodrigues, Irati Macaya, Sarah Bazzocco, Rocco Mazzolini, Elena Andretta et al. (2014) RHOA inactivation enhances Wnt signalling and promotes colorectal cancer. Nat Commun 5: 5458. [Crossref]
17. R Mir, S J Pradhan, P Patil, R Mulherkar, S Galande (2016) Wnt/β-catenin signaling regulated SATB1 promotes colorectal cancer tumorigenesis and progression. Oncogene 35: 1679-1691. [Crossref]
18. Lara Planas Paz, Vanessa Orsini, Luke Boulter, Diego Calabrese, Monika Pikiolek et al. (2016) The RSPO-LGR4/5-ZNRF3/RNF43 module controls liver zonation and size. Nat Cell Biol 18: 467-479. [Crossref]
19. Jing Yang, Laura E Mowry, Kari Nichole Nejak Bowen, Hirohisa Okabe, Cassandra R Diegel et al. (2014) Beta-Catenin Signaling in Murine Liver Zonation and Regeneration: A Wnt-Wnt Situation! Hepatology 60: 964-976. [Crossref]
20. Jack R Wands, Miran Kim (2014) WNT/β-Catenin Signaling and Hepatocellular Carcinoma. Hepatology 60: 452-454.
21. Andreas Schmidt, Albert Braeuning, Peter Ruck, Guido Seitz, Sorin Armeanu Ebinger et al. (2011) Differential expression of glutamine synthetase and cytochrome P450 isoforms in human hepatoblastoma. Toxicology 281: 7-14. [Crossref]
22. Naomoto Harada, Hiroko Oshima, Masahiro Katoh, Yositaka Tamai, Masanobu Oshima et al. (2004) Hepatocarcinogenesis in Mice with -Catenin and Ha-Ras Gene Mutations. Cancer Res 64: 48-54. [Crossref]
23. Junyan Tao, Emily Xu, Yifei Zhao, Sucha Singh, Xiaolei Li et al. (2016) Modeling a Human Hepatocellular Carcinoma Subset in Mice Through Coexpression of Met and Point-Mutant b-Catenin. Hepatology 64: 1587-1605. [Crossref]
24. Sabine Colnot (2016) Focusing on Beta-Catenin Activating Mutations to Refine Liver Tumor Profiling. Hepatology 64: 1850-1852. [Crossref]
25. Jiayi Wang, Joo Seop Park, Yingying Wei, Mihir Rajurkar, Jennifer L Cotton et al. (2013) TRIB2 Acts Downstream of Wnt/TCF in Liver Cancer Cells to Regulate YAP and C/EBPa Function. Mol Cell 51: 211-225. [Crossref]
26. Shanshan Xu, Minghong Tong, Jingqin Huang, Yue Zhang, Yongxia Qiao et al. (2014) TRIB2 inhibits Wnt/b-Catenin/TCF4 signaling through its associated ubiquitin E3 ligases, b-TrCP, COP1 and Smurf1, in liver cancer cells. FEBS Lett 588: 4334-4341. [Crossref]
27. Wei Gao, Zhewei Tang, Yi Fan Zhang, Mingqian Feng, Min Qian et al. (2015) Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis. Nat Commun 6: 6536. [Crossref]
28. Fubo Zhou, Wenting Shang, Xiaoling Yu, Jie Tian (2018) Glypican-3: A promising biomarker for hepatocellular carcinoma diagnosis and treatment. Med Res Rev 38: 741-767. [Crossref]
29. Jianxiang Chen, Muthukumar Rajasekaran, Hongping Xia, Xiaoqian Zhang, Shik Nie Kong et al. (2016) The microtubule-associated protein PRC1 promotes early recurrence of hepatocellular carcinoma in association with the Wnt/β-catenin signalling pathway. Gut 65: 1522-1534. [Crossref]
30. Valentina Angeloni, Paola Tiberio, Valentina Appierto, Maria Grazia Daidone (2015) Implications of stemness-related signaling pathways in breast cancer response to therapy. Semin Cancer Biol 31: 43-51. [Crossref]
31. Babette Schade, Robert Lesurf, Virginie Sanguin Gendreau, Tung Bui, Geneviève Deblois et al. (2013) b-Catenin Signaling Is a Critical Event in ErbB2-Mediated Mammary Tumor Progression. Cancer Res 73: 4474-4487. [Crossref]
32. Luis E Arias Romero, Olga Villamar Cruz, Min Huang, Klaus P Hoeflich, Jonathan Chernoff et al. (2013) Pak1 Kinase Links ErbB2 to b-Catenin in Transformation of Breast Epithelial Cells. Cancer Res 73: 3671-3682. [Crossref]
33. Junchao Cai, Hongyu Guan, Lishan Fang, Yi Yang, Xun Zhu et al. (2013) MicroRNA-374a activates Wnt/β-catenin signaling to promote breast cancer metastasis. J Clin Invest 123: 566-579. [Crossref]
34. Liangliang Ren, Han Chen, Junwei Song, Xuhong Chen, Chun Lin et al. (2019) MiR-454-3p-Mediated Wnt/β-catenin Signaling Antagonists Suppression Promotes Breast Cancer Metastasis. Theranostics 9: 449-465. [Crossref]
35. Mengwei Li, Yanzhen Han, Haoze Zhou, Xin Li, Chenyu Lin et al. (2018) Transmembrane protein 170B is a novel breast tumorigenesis suppressor gene that inhibits the Wnt/β-catenin pathway. Cell Death Dis 9: 91. [Crossref]
36. Chang Gong, Shaohua Qu, Xiao Bin Lv, Bodu Liu, Weige Tan et al. (2014) BRMS1L suppresses breast cancer metastasis by inducing epigenetic silence of FZD10. Nat Commun 5: 5406. [Crossref]
37. Xueqian Zhuang, Hao Zhang, Xiaoyan Li, Xiaoxun Li, Min Cong et al. (2017) Differential effects on lung and bone metastasis of breast cancer by Wnt signalling inhibitor DKK1. Nat Cell Biol 19: 1274-1285. [Crossref]
38. Yaser Atlasi, Leendert Looijenga, Riccardo Fodde (2014) Cancer Stem Cells, Pluripotency, and Cellular Heterogeneity: A WNTer Perspective. Current Topics in Developmental Biology 107: 373-404. [Crossref]
39. Felipe de Sousa e Melo, Antonina V Kurtova, Jonathan M Harnoss, Noelyn Kljavin, Joerg D Hoeck et al. (2017) A distinct role for Lgr5⁺ stem cells in primary and metastatic colon cancer. Nature 543: 676-680. [Crossref]
40. Sarah Schwitalla, Alexander A Fingerle, Patrizia Cammareri, Tim Nebelsiek, Serkan I Göktuna et al. (2013) Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 152: 25-38. [Crossref]
41. D J Huels, O J Sansom (2015) Stem vs non-stem cell origin of colorectal cancer. Br J Cancer 113: 1-5. [Crossref]
42. Soona Shin, Kirk J Wangensteen, Monica Teta Bissett, Yue J Wang, Elham Mosleh Shirazi et al. (2016) Genetic Lineage Tracing Analysis of the Cell of Origin of Hepatotoxin-Induced Liver Tumors in Mice. Hepatology 64: 1163-1177. [Crossref]
43. Amy Reilein, David Melamed, Karen Sophia Park, Ari Berg, Elisa Cimetta et al. (2017) Alternative direct stem cell derivatives defined by stem cell location and graded Wnt signalling. Nat Cell Biol 19: 433-444. [Crossref]
44. Yi Wen Chang, Ying Jhen Su, Michael Hsiao, Kuo Chen Wei, Wei Hsin Lin et al. (2015) Diverse Targets of β-Catenin during the Epithelial-Mesenchymal Transition Define Cancer Stem Cells and Predict Disease Relapse. Cancer Res 75: 3398-3410. [Crossref]
45. Srinivas Malladi, Danilo G Macalinao, Xin Jin, Lan He, Harihar Basnet et al. (2016) Metastatic Latency and Immune Evasion through Autocrine Inhibition of WNT. Cell 165: 45-60. [Crossref]
46. Paloma Ordóñez Morán, Caroline Dafflon, Masamichi Imajo, Eisuke Nishida, Joerg Huelsken (2015) HOXA5 Counteracts Stem Cell Traits by Inhibiting Wnt Signaling in Colorectal Cancer. Cancer Cell 28: 815-829. [Crossref]
47. Si Hui Tan, Nick Barker (2015) Stemming Colorectal Cancer Growth and Metastasis: HOXA5 Forces Cancer Stem Cells to Differentiate. Cancer Cell 28: 683-685. [Crossref]
48. Naoko Takebe, Lucio Miele, Pamela Jo Harris, Woondong Jeong, Hideaki Bando et al. (2015) Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol 12: 445-464. [Crossref]
49. Jun Liu, Shifeng Pan, Mindy H Hsieh, Nicholas Ng, Fangxian Sun et al. (2013) Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc Natl Acad Sci U S A 110: 20224-20229. [Crossref]
50. Kyle David Proffitt, Babita Madan, Zhiyuan Ke, Vishal Pendharkar, Lijun Ding et al. (2013) Pharmacological Inhibition of the Wnt Acyltransferase PORCN Prevents Growth of WNT-Driven Mammary Cancer. Cancer Res 73: 502-507. [Crossref]
51. Phuong N Le, Jessica D McDermott, Antonio Jimeno (2015) Targeting the Wnt pathway in human cancers: Therapeutic targeting with a focus on OMP-54F28. Pharmacol Ther 146: 1-11. [Crossref]
52. F Neri, D Dettori, D Incarnato, A Krepelova, S Rapelli et al. (2015) TET1 is a tumour suppressor that inhibits colon cancer growth by derepressing inhibitors of the WNT pathway. Oncogene 34: 4168-4176. [Crossref]
53. Hongying Duan, Zhiqiang Yan, Wei Chen, Yu Wu, Jinsong Han et al. (2017) TET1 inhibits EMT of ovarian cancer cells through activating Wnt/β-catenin signaling inhibitors DKK1 and SFRP2. Gynecol Oncol 147: 408-417. [Crossref]
54. Ted Lau, Emily Chan, Marinella Callow, Jo Waaler, Jason Boggs et al. (2013) A Novel Tankyrase Small-Molecule Inhibitor Suppresses APC Mutation-Driven Colorectal Tumor Growth. Cancer Res 73: 3132-3144. [Crossref]
55. Martina Ferri, Paride Liscio, Andrea Carotti, Stefania Asciutti, Roccaldo Sardella et al. (2017) Targeting Wnt-driven cancers: Discovery of novel tankyrase inhibitors. Euro J Med Chem 142: 506-522. [Crossref]
56. Oriol Arqués, Irene Chicote, Isabel Puig, Stephan P Tenbaum, Guillem Argilés et al. (2016) Tankyrase inhibition blocks Wnt/β-catenin pathway and reverts resistance to PI3K and AKT inhibitors in the treatment of colorectal cancer. Clin Cancer Res 22: 644-656. [Crossref]
57. Jo Waaler, Ondrej Machon, Lucie Tumova, Huyen Dinh, Vladimir Korinek et al. (2012) A Novel Tankyrase Inhibitor Decreases Canonical Wnt Signaling in Colon Carcinoma Cells and Reduces Tumor Growth in Conditional APC Mutant Mice. Cancer Res 72: 2822-2832. [Crossref]
58. Tao An, Yaxiao Gong, Xue Li, Lingmei Kong, Pengcheng Ma et al. (2017) USP7 inhibitor P5091 inhibits Wnt signaling and colorectal tumor growth. Biochem Pharmacol 131: 29-39. [Crossref]
59. Yi Qu, Jan Roger Olsen, Xing Yuan, Phil F Cheng, Mitchell P Levesque et al. (2018) small molecule promotes b-catenin citrullination and inhibits Wnt signaling in cancer. Nat Chem Biol 14: 94-101. [Crossref]
60. Mari Masuda, Masaaki Sawa, Tesshi Yamada (2015) Therapeutic targets in the Wnt signaling pathway: Feasibility of targeting TNIK in colorectal cancer. Pharmacol Ther 156: 1-9. [Crossref]
61. Guo Dong Ye, Guang Bin Sun, Peng Jiao, Chen Chen, Qing Feng Liu et al. (2016) OVOL2, an Inhibitor of WNT Signaling, Reduces Invasive Activities of Human and Mouse Cancer Cells and is Downregulated in Human Colorectal Tumors. Gastroenterology 150: 659-671. [Crossref]