REGULATION OF NON-CANONICAL WNT SIGNALING PATHWAY IN STEM CELLS DEVELOPMENT AND CARCINOGENESIS

REGULATION OF NON-CANONICAL WNT SIGNALING PATHWAY IN STEM CELLS DEVELOPMENT AND CARCINOGENESIS

Rajendran Prakash^*1 and Rattinam Rajesh ²

Department of Biotechnology, VMKV Engineering College, Vinayaka Missions University ¹, Salem, TN, India.

Department of Microbial Biotechnology, Bharathiar University ², Coimbatore, TN, India.

ABSTRACT: Since 1982, Wnt1 (Wingless int-1) was first identified in mammary carcinoma. Further, Wnt signaling pathway was discovered. Wnt signals were involved in stem cells development, regeneration, cell cycle and repair mechanism. Finally abnormality Wnt signals were stimulated variety of cancers. Especially, non-canonical signaling pathways such as Wnt/PCP and Wnt/Ca2+ pathway were involved in development process. These pathways regulated stem cells and organ development such as cell polarity, adhesion, cell shape and cell movement. Despite, aberrant expression of non-canonical pathway induced tumorigenesis in development. In clinical studies, drugs were developed against cancer cells not in cancer stem cells. Drugs will synthesis against cancer stem cells based on the activation of abnormality of Wnt signaling.

Wnt1, non-canonical pathway,

stem cells development, tumorigenesis, drugs.

INTRODUCTION: Organ development, stem cells have ability to self-renewal and proliferate normal to mature cell types. Stem cells have been developed adult organ from pluripotent stem cells. Many signals were involved in the development and carcinogenesis ¹. Wnt (Wingless int-1) gene was first identified as int-1 gene by activation of mouse mammary tumor virus (MMTV). Finally, full circulations of Wnt signaling pathways were developed in stem cells and cancer development ^{2, 3}.Wnt signals play crucial role in stem cells development and tumorigenesis. Wnt signals expressed both of stem cells and cancer stem cells (CSCs). Wnt signals classified as canonical and non-canonical pathway.

Further non-canonical pathway consists of Wnt/Planer cell polarity (PCP) pathway and Wnt/Ca²⁺ signaling pathway. PCP and Ca²⁺ signals were regulated variety of stem cells and organ developments. Despite, abnormalities of non-canonical Wnt signals regulated many types of cancer development ^{4, 5}.

Non-canonical Wnt/PCP signaling pathway

The Wnt/PCP pathway was involved in stem cells development such as cell polarity, adhesion, and shape and cell movement. Regulation of PCP pathway not required β-catenin and it was first identified in Drosophila. This PCP pathway was inhibited nuclear activity of β-catenin and stimulation of PCP pathway not required low density lipoprotein receptor (LRP) as a co-receptor.

The complex of Wnt proteins and frizzed heterodimeric receptor (FZD) were triggered the regulation of Wnt/PCP signaling pathway. This complex Wnt-FZD recruits Dishevelled (Dsh) to enhanced signaling pathway. Activated Dsh bind with Dishevelled-associated activator of morphogenesis 1 (DAMM1). Daam1 activated G-protein Rho through guanine exchange factor (GTP) then Rho stimulated Rho-associated kinase (ROCK). Dsh was also regulated Dsh-Rac1 and mediated profilin and actin complex.

This profilin and actin complex enhanced restructuring of the cytoskeleton and gastrulation. Rac1 also involved in the activation of JNK which lead to actin polymerization and also JNK stimulated gene transcription such as c-jun (Figure1). PCP pathway has crucial role in stem cells and development such as angiogenesis, bone morphogenesis, gastrulation ^{6, 7}.

FIGURE 1: NON-CANONICAL WNT/PLANER CELL POLARITY (PCP) SIGNALING PATHWAY IN DEVELOPMENT

Non-canonical Wnt/Ca²⁺ signaling pathway

Wnt/Ca²⁺ signaling pathway mostly induced by Wnt5a and Wnt5b proteins which mediated the synthesis of secondary messenger such as calcium. Finally, this secondary messenger signaling pathway described as Wnt/Ca²⁺ signaling pathway. Wnt/Ca²⁺ signal also not required β-catenin and calcium released from endoplasmic reticulum (ER) to control intracellular Ca²⁺ levels. Wnt-FZD complex directly activated trimeric G-protein. Dsh and G-protein complex stimulated the activation of PIP2 and activated PIP2 was cleaved into DAG and inositol 1, 4, 5-trisphosphate (IP3). And another way inactivation of PKG or elevation of IP3 regulated calcium from ER ^{6, 7}.

FIGURE 2: NON-CANONICAL WNT/ CA²⁺ SIGNALING PATHWAY IN DEVELOPMENT

DAG was activated cdc42 which commonly regulated ventral patterning. High level of calcium ions stimulated calcineurin and CaMKII activation through calmodulin. Calcineurin also activated nuclear factor of activated T cells (NFAT), which regulated ventral patterning, cell adhesion, migration and tissues separation. CaMKII was activated MAPK signaling and it was also activated TGF-b-activated kinase (TAK1). NLK expression was induced by TAK1 and NLK act as an antagonist of Wnt/ β-catenin signaling pathway (Figure 2). Despite, Inhibition of calcium release occurred from ER by activated PDE ^{6, 8}.

 Non-canonical Wnt signaling in Stem cells and development

Wnt signals have crucial impact in organ development from non-vertebrates to vertebrates.

Especially, non-canonical Wnt signaling have specialized function in stem cells and development such as cell fate, cell proliferation and differentiation, cell survival and apoptosis, cell behavior, cell adhesion, migration and tissues separation and ventral patterning ⁹.

Non-canonical signaling pathways also regulated self-renewal, differentiation and proliferation (Table 1). Both of Wnt/PCP pathway and Wnt/Ca²⁺ signaling pathway have specialized role in development (Table 2). Commonly, these pathways regulated variety of stem cells to development such as central nervous system development, Limb, facial, digestive tract, genitourinary, cardiogenesis and spermatogenesis and skeletogenesis ⁷.

TABLE 1: NON-CANONICAL WNT/PCP SIGNALING PATHWAY IN STEM CELLS AND DEVELOPMENT

TABLE 2: NON-CANONICAL WNT/CA²⁺ SIGNALING PATHWAY IN STEM CELLS AND DEVELOPMENT

Non-canonical Wnt signaling in carcinogenesis

Non-canonical Wnt signaling pathways also involved in cancer development. Abnormality of non-canonical Wnt signaling induced tumorigenesis in development process. Wnt1 was first identified ongogene in mammary carcinomas ². Many deregulation of Wnt signals stimulated unwanted vast cell growth and movement. Cancer was one of critical problem in human world. Aberrant expression of non-canonical Wnt signals

were regulated various cancers such as mammary carcinogenesis, prostate cancer, colon carcinoma, pancreatic cancer, cervical and renal cell carcinoma, hepatocellularcarcinoma, gastric and oral squamous cell carcinoma. These are few types of cancer regulated by deregulation of non-canonical Wnt signaling.

TABLE 3: NON-CANONICAL WNT/PCP SIGNALING PATHWAY IN CARCINOGENESIS

In Wnt/PCP signaling, Wnt5a and Wnt5b to regulated metastasis of melanoma, gastric and breast cancer by overexpression of Rac and JNK and also play critical role in metastasis of sarcoma.

Clinical studies, Dsh1 and Dsh3 highly expressed in cancer metastasis, mainly in non-small cell lung cancer. Damm1, Rac, JNK, Rock and profilin were involved in the upregulation of cancer ⁹ (Table 3).

TABLE 4: NON-CANONICAL WNT/CA²⁺ SIGNALING PATHWAY IN CARCINOGENESIS

In Wnt/Ca²⁺ signal, Wnt5a and Wnt5b act as a proto-ongogene in breast cancer, pancreatic cancer, prostate cancer, melanoma and tumor suppressor gene in neuroblastoma, breast cancer, acute myeloid lymphoma, colon carcinoma, esophageal squamous cell carcinoma and thyroid carcinoma ⁸ (Table 4).

 Future research

Wnt signals plays important role in organogenesis and cancer development. Abnormalities of non-canonical Wnt signal majorly regulated various cancer. Many drugs were developed against cancer based on abnormality of Wnt signals. Cancer therapy was also inhibited or killed cancer cells but

not in cancer stem cells. These Cancer stem cells were regulated vast cancer cell growth and proliferation. So new drugs are need to synthesis, especially to kill cancer stem cells. Herbal drugs were highly expressed and killed cancer cells without side effect. New drugs will develop against cancer stem cells based on deregulation of non-canonical Wnt signaling pathways.

 ACKNOWLEDGEMENTS: The author is sincere thank to Dr. A. Nagappan, Principal, Dr. C.K. Hindumathy, Dean- Biosciences andDr. S. Anandakumar, Vinayaka Mission’s Kirupananda Variyar Engineering College, Salem, Tamil Nadu for their support for carry out this work.

REFERENCES:

1. Nusse R and Varmus HE: Wnt genes. Cell 1992; 69:1073-1087.
2. Nusse R and Varmus HE: Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 1982; 31:99-109.
3. Nusse R, Brown A, Papkoff J, Scambler P, Shackleford G, McMahon A, et al: A new nomenclature for int-1 and related genes: the Wnt gene family. Cell 1991; 64:231.
4. Nusse R, Fuerer C, Ching W, Harnish K, Logan C, Zeng A, et al: Wnt signaling and stem cell control. Cold Spring Harb Symp Quant Biol 2008; 73:59-66.
5. Nusse Roel and Varmus Harold: Three decades of Wnts: a personal perspective on how a scientific field developed. The EMBO Journal 2012; 31:2670–84.
6. Zhang X, Hao L, Meng L, Liu M, Zhao L, Hu F, et al: Digital gene expression tag profiling analysis of the gene expression patterns regulating the early stage of mouse spermatogenesis. PLoS One 2013; 8:e58680
7. Sonderegger S, Pollheimer J and Knofler M: Wnt signalling in implantation, decidualisation and placental differentiation--review. Placenta 2010; 31:839-47.
8. De A: Wnt/Ca2+ signaling pathway: a brief overview. Acta Biochim Biophys Sin 2011; 43:745-56.
9. Wang Y: Wnt/Planar cell polarity signaling: A new paradigm for cancer therapy. Mol Cancer Ther 2009; 8:2103-9.
10. Summerhurst K, Stark M, Sharpe J, Davidson D and Murphy P: 3D representation of Wnt and Frizzled gene expression patterns in the mouse embryo at embryonic day 11.5 (Ts19). Gene Expr Patterns 2008; 8:331-48.
11. Cai L, Ye Z, Zhou BY, Mali P, Zhou C and Cheng L: Promoting human embryonic stem cell renewal or differentiations by modulating Wnt signal and culture conditions. Cell Res 2007; 17:62-72.
12. Gozo MC, Aspuria PJ, Cheon DJ, Walts AE, Berel D, Miura N, et al: Foxc2 induces Wnt4 and Bmp4 expression during muscle regeneration and osteogenesis. Cell Death Differ 2013; 20:1031-42.
13. Heinonen KM, Vanegas JR, Lew D, Krosl J and Perreault C: Wnt4 enhances murine hematopoietic progenitor cell expansion through a planar cell polarity-like pathway. PLoS One 2011; 6:e19279.
14. Boyer A, Lapointe E, Zheng X, Cowan RG, Li H, Quirk SM, et al: WNT4 is required for normal ovarian follicle development and female fertility. FASEB J 2010; 24:3010-25.
15. Yeh JR, Zhang X and Nagano MC: Wnt5a is a cell-extrinsic factor that supports self-renewal of mouse spermatogonial stem cells. J Cell Sci 2011; 124:2357-66.
16. Brun J, Fromigue O, Dieudonne FX, Marty C, Chen J, Dahan J, et al: The LIM-only protein FHL2 controls mesenchymal cell osteogenic differentiation and bone formation through Wnt5a and Wnt10b. Bone 2013; 53:6-12.
17. Le Grand F, Jones AE, Seale V, Scime A and Rudnicki MA: Wnt7a activates the planar cell polarity pathway to drive the symmetric expansion of satellite stem cells. Cell Stem Cell 2009; 4:535-47.
18. Kandyba E and Kobielak K: Wnt7b is an important intrinsic regulator of hair follicle stem cell homeostasis and hair follicle cycling. Stem Cells 2013 [Epub ahead of print]
19. Cox AA, Jezewski PA, Fang PK and Payne-Ferreira TL: Zebrafish Wnt9a,9b paralog comparisons suggest ancestral roles for Wnt9 in neural, oral-pharyngeal ectoderm and mesendoderm. Gene Expr Patterns 2010; 10:251-8.
20. Jezewski PA, Fang PK, Payne-Ferreira TL and Yelick PC:  Zebrafish Wnt9b synteny and expression during first and second arch, heart, and pectoral fin bud morphogenesis. Zebrafish 2008 5: 169-77.
21. Yamashiro T, Zheng L, Shitaku Y, Saito M, Tsubakimoto T, Takada K, et al: Wnt10a regulates dentin sialophosphoprotein mRNA expression and possibly links odontoblast differentiation and tooth morphogenesis. Differentiation 2007; 75:452-62.
22. Nusse R, Theunissen H, Wagenaar E, Rijsewijk F, Gennissen A, Otte A, et al: The Wnt-1 (int-1) oncogene promoter and its mechanism of activation by insertion of proviral DNA of the mouse mammary tumor virus. Mol Cell Biol 1990; 10:4170–9.
23. Andrade Filho PA, Letra A, Cramer A, Prasad JL, Garlet GP, Vieira AR, et al: Insights from studies with oral cleft genes suggest associations between WNT-pathway genes and risk of oral cancer. J Dent Res 2011; 90:740-6.
24. Posviatenko AV, Kulikova KV, Gnuchev NV, Georgiev GP, Kibardin AV and Larin SS: Functional properties of the WNT11 new isoform, expressed in colon carcinoma cell line HT29. Mol Biol (Mosk)  2012; 46:129-38.
25. Toyama T, Lee HC, Koga H, Wands JR and Kim M: Noncanonical Wnt11 inhibits hepatocellular carcinoma cell proliferation and migration. Mol Cancer Res. 2010; 8:254-65.
26. Uysal-Onganer P, Kawano Y, Caro M, Walker MM, Diez S, Darrington RS, et al: Wnt-11 promotes neuroendocrine-like differentiation,survival and migration of prostate cancer cells. Mol Cancer 2010; 9:55.
27. Kirikoshi H, Sekihara H and Katoh M: Molecular cloning and characterization of human WNT11. Int J Mol Med 2001; 8:651-6.
28. Bui TD, Zhang L, Rees MC, Bicknell R and Harris AL: Expression and hormone regulation of Wnt2, 3, 4, 5a, 7a, 7b and 10b in normal human endometrium and endometrial carcinoma. Br J Cancer 1997; 75:1131-6.
29. Lu W, Wei W, de Bock GH, Zhou H, Li Q and Shen X: The roles of Wnt5a, JNK and paxillin in the occurrence of metastasis of pancreatic adenocarcinoma. Int J Clin Oncol 2013 [Epub ahead of print]
30. Da Forno PD, Pringle JH, Hutchinson P, Osborn J, Huang Q, Potter L, et al: WNT5A expression increases during melanoma progression and correlates with outcome. Clin Cancer Res 2008; 14:5825-32.
31. Li J, Ying J, Fan Y, Wu L, Ying Y, Chan AT, et al: WNT5A antagonizes WNT/β-catenin signaling and is frequently silenced by promoter CpG methylation in esophageal squamous cell carcinoma. Cancer Biol Ther. 2010; 10:617-24.
32. Leris AC, Roberts TR, Jiang WG, Newbold RF and Mokbel K: WNT5A expression in human breast cancer. Anticancer Res 2005; 25:731-4.
33. Nitzki F, Zibat A, König S, Wijgerde M, Rosenberger A, Brembeck FH, et al: Tumor stroma-derived Wnt5a induces differentiation of basal cell carcinoma of Ptch-mutant mice via CaMKII. Cancer Res 2010; 70:2739-48.
34. Andrade Filho PA, Letra A, Cramer A, Prasad JL, Garlet GP, Vieira AR, et al: Insights from studies with oral cleft genes suggest associations between WNT-pathway genes and risk of oral cancer. J Dent Res 2011; 90:740-6.
35. Topczewski J, Sepich DS, Myers DC, Walker C, Amores A, Lele Z, et al: The zebrafish glypican knypek controls cell polarity during gastrulation movements of convergent extension. Dev Cell 2001; 1:251-64.
36. Rawls AS and Wolff T: Strabismus requires Flamingo and Prickle function to regulate tissue polarity in the Drosophila eye. Development 2003; 130:1877-87.
37. Carreira-Barbosa F, Concha ML, Takeuchi M, Ueno N, Wilson SW and Tada M: Prickle 1 regulates cell movements during gastrulation and neuronal migration in zebrafish. Development 2003; 130:4037-46.
38. Schlessinger K, Hall A and Tolwinski N: Wnt signaling pathways meet Rho GTPases. Genes Dev 2009; 23:265-77.
39. Kilian KA, Bugarija B, Lahn BT and Mrksich M: Geometric cues for directing the differentiation of mesenchymal stem cells. Proc Natl Acad Sci U S A. 2010; 107:4872-7.
40. Liu A, Chen S, Cai S, Dong L, Liu L, Yang Y, et al: Wnt5a through noncanonical Wnt/JNKorWnt/PKC signaling contributes to the differentiation of mesenchymalstem cells into type II alveolar epithelial cells in vitro. PLoS One 2014; 9:e90229.
41. Sancho R, Nateri AS, de Vinuesa AG, Aguilera C, Nye E, Spencer-Dene B, et al: JNK signalling modulates intestinal homeostasis and tumourigenesis in mice. EMBO J 2009; 28:1843-54.
42. Tarfiei G, Noruzinia M, Soleimani M, Kaviani S, Mahmoodinia Maymand M, Farshdousti Hagh M, et al: ROR2 Promoter Methylation Change in Osteoblastic Differentiation of Mesenchymal Stem Cells. Cell J 2011; 13:11-5.
43. Fabian L, Wei HC, Rollins J, Noguchi T, Blankenship JT, Bellamkonda K, et al: Phosphatidylinositol 4,5-bisphosphate directs spermatid cell polarity and exocyst localization in Drosophila. Mol Biol Cell 2010; 21:1546-55.
44. Sun J, He W, Bai SZ, Peng X, Zhang N, Li HX, et al: The expression of calcium-sensing receptor in mouse embryonicstem cells (mESCs) and its influence on differentiation of mESC into cardiomyocytes. Differentiation 2013; 85:32-40.
45. Jia Y, Loison F, Hattori H, Li Y, Erneux C, Park SY, et al: Inositol trisphosphate 3-kinase B (InsP3KB) as a physiological modulator of myelopoiesis. Proc Natl Acad Sci U S A 2008; 105:4739-44.
46. Florian MC, Dorr K, Niebel A, Daria D, Schrezenmeier H, Rojewski M, et al: Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation. Cell Stem Cell 2012; 10:520-30.
47. Wu X, Quondamatteo F, Lefever T, Czuchra A, Meyer H, Chrostek A, et al: Cdc42 controls progenitor cell differentiation and beta-catenin turnover in skin. Genes Dev 2006; 20:571-85.
48. Kuhl M, Sheldahl LC, Malbon CC and Moon RT: Ca(2+)/calmodulin-dependent protein kinase II is stimulated by Wnt and Frizzled homologs and promotes ventral cell fates in Xenopus. J Biol Chem 2000; 275:12701-11.
49. Fazzi R, Pacini S, Carnicelli V, Trombi L, Montali M, Lazzarini E, et al: Mesodermal progenitor cells (MPCs) differentiate into mesenchymal stromal cells (MSCs) by activation of Wnt5/calmodulin signalling pathway. PLoS One 2011; 6:e25600.
50. Parri M and Chiarugi P: Rac and Rho GTPases in cancer cell motility control. Cell Commun Signal 2010; 8:23.
51. Vega FM, Fruhwirth G, Ng T and Ridley AJ: RhoA and RhoC have distinct roles in migrations and invasion by acting through different targets. J Cell Biol 2011; 193:655-65.
52. Hwang H, Kim EK, Park J, Suh PG and Cho YK: RhoA and Rac1 play independent roles in lysophosphatidic acid-induced ovarian cancer chemotaxis. Integr Biol (Camb)2014; 6:267-76.
53. Vigil D, Kim TY, Plachco A, Garton AJ, Castaldo L, Pachter JA, et al: ROCK1 and ROCK2 are required for non-small cell lung canceranchorage-independent growth and invasion. Cancer Res 2012; 72:5338-47.
54. Das M, Garlick DS, Greiner DL and Davis RJ: The role of JNK in the development of hepatocellular carcinoma. Genes Dev 2011; 25:634-45.
55. Wei W, Li H, Li N, Sun H, Li Q and Shen X: WNT5A/JNK signaling regulates pancreatic cancer cells migration by Phosphorylating Paxillin. Pancreatology 2013; 13:384-92.
56. Hubner A, Mulholland DJ, Standen CL, Karasarides M, Cavanagh-Kyros J, Barrett T, et al: JNK and PTEN cooperatively control the development of invasive adenocarcinoma of the prostate. Proc Natl Acad Sci U S A 2012; 109:12046-51.
57. Wertheimer E, Gutierrez-Uzquiza A, Rosemblit C, Lopez-Haber C, Sosa MS and Kazanietz MG: Rac signaling in breast cancer: a tale of GEFs and GAPs. Cell Signal 2012; 24:353-62.
58. Rebagay G, Yan S, Liu C and Cheung NK: ROR1 and ROR2 in Human Malignancies: Potentials for Targeted Therapy. Front Oncol 2012; 2:34.
59. Thapa N and Anderson RA: PIP2 signaling, an integrator of cell polarity and vesicle trafficking in directionally migrating cells. Cell Adh Migr 2012; 6:409-12.
60. Pierro C, Cook SJ, Foets TC, Bootman MD and Roderick HL: Oncogenic K-Ras suppresses IP₃-dependent Ca²⁺ release through remodelling of the isoform composition of IP₃Rs and ER luminal Ca²⁺ levels in colorectal cancer cell lines. J Cell Sci 2014; 127:1607-19.
61. Beverly A and Teicher: Protein Kinase C as a Therapeutic Target. Clin Cancer Res 2006; 12:5336-45.
62. Rodriguez-Mora OG, LaHair MM, McCubrey JA and Franklin RA: Calcium/calmodulin-dependent kinase I and calcium/calmodulin-dependent kinase kinase participate in the control of cell cycle progression in MCF-7 human breast cancer cells. Cancer Res 2005; 65:5408-16.
63. Karacosta LG, Foster BA, Azabdaftari G, Feliciano DM and Edelman AM: A regulatory feedback loop between Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2) and the androgen receptor in prostate cancer progression. J Biol Chem 2012; 287:24832-43.
    

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    Prakash R and Rajesh R: Regulation of Non-Canonical Wnt Signaling Pathway in Stem Cells Development and Carcinogenesis. Int J Pharm Sci Res2015; 6(1): 85-90.doi: 10.13040/IJPSR.0975-8232.6 (1).85-90.

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