非经典Wnt通路在卵巢癌中的作用与潜在治疗意义研究进展

doi:10.3969/j.issn.1674-8115.2023.08.015

摘要/Abstract

摘要：

卵巢癌是病死率最高的女性生殖系统恶性肿瘤，其发生发展过程涉及多种信号通路的异常调控。Wnt信号通路是一种高度保守的分子信号通路，在胚胎发育、组织稳态以及肿瘤发生发展等生理及病理过程中发挥重要作用。Wnt信号通路包括经典的Wnt/β-连环蛋白（β-catenin）通路以及不依赖β-catenin转录活性的非经典Wnt通路，后者主要包括Wnt/平面细胞极性（Wnt/planar cell polarity，Wnt/PCP）通路和Wnt/Ca²⁺通路。以往研究主要集中于经典Wnt通路与肿瘤进展的关系，但近年来非经典Wnt通路逐渐受到重视，相关研究丰富了其在组织发育及肿瘤发生等生理及病理过程中的认知。现有研究提示，非经典Wnt通路在卵巢癌中受到异常调控，并与卵巢癌的分期及预后密切相关。非经典Wnt通路在卵巢癌细胞增殖、迁移、侵袭等多种生物学过程发挥重要作用，且该通路的变化与卵巢癌化学治疗（化疗）耐药也具有一定相关性。该文从上述多个角度对非经典Wnt通路在卵巢癌中的作用进行综述，并讨论基于非经典Wnt通路的卵巢癌靶向治疗研究进展，为开发新型靶向药物提供新的思路。

关键词: 卵巢癌, 非经典Wnt通路, 肿瘤进展, 化疗耐药, 靶向治疗

Abstract:

Ovarian cancer is a malignant tumor of the female reproductive system with the highest mortality, and involves the aberrant regulation of multiple molecular signaling pathways. As a highly conserved molecular pathway, Wnt signaling pathway plays an important role in embryonic development, tissue homeostasis, and tumorigenesis. Wnt signaling pathway includes canonical Wnt/β-catenin pathway and non-canonical pathway, and the latter mainly includes Wnt/planar cell polarity (Wnt/PCP) pathway and Wnt/Ca²⁺ pathway. Previous studies have mainly focused on the relationship between the canonical Wnt pathway and tumor progression. Recently, the non-canonical Wnt pathway has gradually received attention, and related researches have enriched the understanding of the non-canonical Wnt pathway in physiological and pathological processes such as tissue development and tumorigenesis. The existing studies suggest that the nonclassical Wnt pathway is abnormally regulated in ovarian cancer and is closely related to the staging and prognosis of ovarian cancer. Non-classical Wnt pathway plays an important role in many biological processes such as proliferation, migration and invasion of ovarian cancer cells, and the changes of this pathway are also related to chemotherapy resistance of ovarian cancer. This article reviews the role of the non-canonical Wnt pathway in ovarian cancer, and discusses the research progress of targeted therapy based on the non-canonical Wnt pathway, aiming to provide new ideas for the development of novel targeted drugs.

Key words: ovarian cancer, non-canonical Wnt pathway, cancer progression, chemotherapy resistance, targeted therapy

中图分类号:

R737.31

周婉桢, 滕银成. 非经典Wnt通路在卵巢癌中的作用与潜在治疗意义研究进展[J]. 上海交通大学学报（医学版）, 2023, 43(8): 1056-1063.

ZHOU Wanzhen, TENG Yincheng. Research progress of the role of non-canonical Wnt signaling pathway in ovarian cancer and its potential therapeutic implications[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(8): 1056-1063.

图/表 1

参考文献 53

1	SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249.
2	ZHANG Y, WANG X. Targeting the Wnt/β-catenin signaling pathway in cancer[J]. J Hematol Oncol, 2020, 13(1): 165.
3	NGUYEN V H L, HOUGH R, BERNAUDO S, et al. Wnt/β-catenin signalling in ovarian cancer: insights into its hyperactivation and function in tumorigenesis[J]. J Ovarian Res, 2019, 12(1): 122.
4	KONI M, PINNARÒ V, BRIZZI M F. The Wnt signalling pathway: a tailored target in cancer[J]. Int J Mol Sci, 2020, 21(20): 7697.
5	ASEM M S, BUECHLER S, WATES R B, et al. Wnt5a signaling in cancer[J]. Cancers (Basel), 2016, 8(9): 79.
6	VANDERVORST K, HATAKEYAMA J, BERG A, et al. Cellular and molecular mechanisms underlying planar cell polarity pathway contributions to cancer malignancy[J]. Semin Cell Dev Biol, 2018, 81: 78-87.
7	BUENO M L P, SAAD S T O, ROVERSI F M. Wnt5a in tumor development and progression: a comprehensive review[J]. Biomed Pharmacother, 2022, 155: 113599.
8	LOJK J, MARC J. Roles of non-canonical Wnt signalling pathways in bone biology[J]. Int J Mol Sci, 2021, 22(19): 10840.
9	FORD C E, PUNNIA-MOORTHY G, HENRY C E, et al. The non-canonical Wnt ligand, Wnt5a, is upregulated and associated with epithelial to mesenchymal transition in epithelial ovarian cancer[J]. Gynecol Oncol, 2014, 134(2): 338-345.
10	PENG C J, ZHANG X L, YU H L, et al. Wnt5a as a predictor in poor clinical outcome of patients and a mediator in chemoresistance of ovarian cancer[J]. Int J Gynecol Cancer, 2011, 21(2): 280-288.
11	JIN P, SONG Y, YU G Y. The role of abnormal methylation of Wnt5a gene promoter regions in human epithelial ovarian cancer: a clinical and experimental study[J]. Anal Cell Pathol (Amst), 2018, 2018: 6567081.
12	HENRY C E, LLAMOSAS E, DJORDJEVIC A, et al. Migration and invasion is inhibited by silencing ROR1 and ROR2 in chemoresistant ovarian cancer[J]. Oncogenesis, 2016, 5(5): e226.
13	ZHANG H L, QIU J R, YE C P, et al. ROR1 expression correlated with poor clinical outcome in human ovarian cancer[J]. Sci Rep, 2014, 4: 5811.
14	KARIN-KUJUNDZIC V, KARDUM V, SOLA I M, et al. Dishevelled family proteins in serous ovarian carcinomas: a clinicopathologic and molecular study[J]. APMIS, 2020, 128(3): 201-210.
15	LIU R, CHENG J L, CHEN Y N, et al. Potential role and prognostic importance of dishevelled-2 in epithelial ovarian cancer[J]. Int J Gynaecol Obstet, 2017, 138(3): 304-310.
16	XU W W, GU J J, REN Q L, et al. NFATC1 promotes cell growth and tumorigenesis in ovarian cancer up-regulating c-Myc through ERK1/2/p38 MAPK signal pathway[J]. Tumor Biol, 2016, 37(4): 4493-4500.
17	XIN B, JI K Q, LIU Y S, et al. NFAT overexpression correlates with CA72-4 and poor prognosis of ovarian clear-cell carcinoma subtype[J]. Reprod Sci, 2021, 28(3): 745-756.
18	CHEN S, WANG J, GOU W F, et al. The involvement of RhoA and Wnt5a in the tumorigenesis and progression of ovarian epithelial carcinoma[J]. Int J Mol Sci, 2013, 14(12): 24187-24199.
19	CHEHOVER M, REICH R, DAVIDSON B. Expression of Wnt pathway molecules is associated with disease outcome in metastatic high-grade serous carcinoma[J]. Virchows Arch, 2020, 477(2): 249-258.
20	KOTRBOVÁ A, OVESNÁ P, GYBEL' T, et al. WNT signaling inducing activity in ascites predicts poor outcome in ovarian cancer[J]. Theranostics, 2020, 10(2): 537-552.
21	AZIMIAN-ZAVAREH V, DEHGHANI-GHOBADI Z, EBRAHIMI M, et al. Wnt5a modulates integrin expression in a receptor-dependent manner in ovarian cancer cells[J]. Sci Rep, 2021, 11(1): 5885.
22	MENCK K, HEINRICHS S, BADEN C, et al. The WNT/ROR pathway in cancer: from signaling to therapeutic intervention[J]. Cells, 2021, 10(1): 142.
23	HENRY C E, EMMANUEL C, LAMBIE N, et al. Distinct patterns of stromal and tumor expression of ROR1 and ROR2 in histological subtypes of epithelial ovarian cancer[J]. Transl Oncol, 2017, 10(3): 346-356.
24	ZHANG S P, CUI B, LAI H, et al. Ovarian cancer stem cells express ROR1, which can be targeted for anti-cancer-stem-cell therapy[J]. Proc Natl Acad Sci USA, 2014, 111(48): 17266-17271.
25	FANG X, CHEN C Q, XIA F Z, et al. CD274 promotes cell cycle entry of leukemia-initiating cells through JNK/cyclin D2 signaling[J]. J Hematol Oncol, 2016, 9(1): 124.
26	ASEM M, YOUNG A M, OYAMA C, et al. Host Wnt5a potentiates microenvironmental regulation of ovarian cancer metastasis[J]. Cancer Res, 2020, 80(5): 1156-1170.
27	LUO M, ZHOU L, ZHAN S J, et al. ALPL regulates the aggressive potential of high grade serous ovarian cancer cells via a non-canonical Wnt pathway[J]. Biochem Biophys Res Commun, 2019, 513(2): 528-533.
28	QI H, SUN B C, ZHAO X L, et al. Wnt5a promotes vasculogenic mimicry and epithelial-mesenchymal transition via protein kinase Cα in epithelial ovarian cancer[J]. Oncol Rep, 2014, 32(2): 771-779.
29	AL-ALEM L F, MCCORD L A, SOUTHARD R C, et al. Activation of the PKC pathway stimulates ovarian cancer cell proliferation, migration, and expression of MMP7 and MMP10[J]. Biol Reprod, 2013, 89(3): 73.
30	TANG Y Y, HE Y, ZHANG P, et al. LncRNAs regulate the cytoskeleton and related Rho/ROCK signaling in cancer metastasis[J]. Mol Cancer, 2018, 17(1): 77.
31	WANG S Z, WEI H, ZHANG S L. Dickkopf-4 is frequently overexpressed in epithelial ovarian carcinoma and promotes tumor invasion[J]. BMC Cancer, 2017, 17(1): 455.
32	DEHGHANI-GHOBADI Z, SHEIKH HASANI S, AREFIAN E, et al. Wnt5a and TGFβ1 converges through YAP1 activity and integrin alpha v up-regulation promoting epithelial to mesenchymal transition in ovarian cancer cells and mesothelial cell activation[J]. Cells, 2022, 11(2): 237.
33	PARK H W, KIM Y C, YU B, et al. Alternative Wnt signaling activates YAP/TAZ[J]. Cell, 2015, 162(4): 780-794.
34	VESKIMÄE K, SCARAVILLI M, NIININEN W, et al. Expression analysis of platinum sensitive and resistant epithelial ovarian cancer patient samples reveals new candidates for targeted therapies[J]. Transl Oncol, 2018, 11(5): 1160-1170.
35	HUNG T H, HSU S C, CHENG C Y, et al. Wnt5a regulates ABCB1 expression in multidrug-resistant cancer cells through activation of the non-canonical PKA/β-catenin pathway[J]. Oncotarget, 2014, 5(23): 12273-12290.
36	ZHANG K, SONG H X, YANG P, et al. Silencing dishevelled-1 sensitizes paclitaxel-resistant human ovarian cancer cells via AKT/GSK-3β/β-catenin signalling[J]. Cell Prolif, 2015, 48(2): 249-258.
37	HUANG L, JIN Y, FENG S J, et al. Role of Wnt/β-catenin, Wnt/c-Jun N-terminal kinase and Wnt/Ca²⁺ pathways in cisplatin-induced chemoresistance in ovarian cancer[J]. Exp Ther Med, 2016, 12(6): 3851-3858.
38	HUANG W, YANG S, CHENG Y S, et al. Terfenadine resensitizes doxorubicin activity in drug-resistant ovarian cancer cells via an inhibition of CaMKⅡ/CREB1 mediated ABCB1 expression[J]. Front Oncol, 2022, 12: 1068443.
39	WANG Y L, XU C L, WANG Y, et al. MicroRNA-365 inhibits ovarian cancer progression by targeting Wnt5a[J]. Am J Cancer Res, 2017, 7(5): 1096-1106.
40	JENEI V, SHERWOOD V, HOWLIN J, et al. A t-butyloxycarbonyl-modified Wnt5a-derived hexapeptide functions as a potent antagonist of Wnt5a-dependent melanoma cell invasion[J]. Proc Natl Acad Sci USA, 2009, 106(46): 19473-19478.
41	MOORE K N, GUNDERSON C C, SABBATINI P, et al. A phase 1b dose escalation study of ipafricept (OMP54F28) in combination with paclitaxel and carboplatin in patients with recurrent platinum-sensitive ovarian cancer[J]. Gynecol Oncol, 2019, 154(2): 294-301.
42	CHOI M Y, WIDHOPF G F Ⅱ, WU C C, et al. Pre-clinical specificity and safety of UC-961, a first-in-class monoclonal antibody targeting ROR1[J]. Clin Lymphoma Myeloma Leuk, 2015, 15: S167-S169.
43	CHOI M Y, WIDHOPF G F Ⅱ, GHIA E M, et al. Phase Ⅰ trial: cirmtuzumab inhibits ROR1 signaling and stemness signatures in patients with chronic lymphocytic leukemia[J]. Cell Stem Cell, 2018, 22(6): 951-959.e3.
44	GHIA E M, RASSENTI L Z, CHOI M Y, et al. High expression level of ROR1 and ROR1-signaling associates with venetoclax resistance in chronic lymphocytic leukemia[J]. Leukemia, 2022, 36(6): 1609-1618.
45	ZHANG S P, ZHANG H, GHIA E M, et al. Inhibition of chemotherapy resistant breast cancer stem cells by a ROR1 specific antibody[J]. Proc Natl Acad Sci USA, 2019, 116(4): 1370-1377.
46	LIU D L, KAUFMANN G F, BREITMEYER J B, et al. The anti-ROR1 monoclonal antibody zilovertamab inhibits the proliferation of ovarian and endometrial cancer cells[J]. Pharmaceutics, 2022, 14(4): 837.
47	WU D, YU X Y, WANG J, et al. Ovarian cancer stem cells with high ROR1 expression serve as a new prophylactic vaccine for ovarian cancer[J]. J Immunol Res, 2019, 2019: 9394615.
48	OSORIO-RODRÍGUEZ D A, CAMACHO B A, RAMÍREZ-SEGURA C. Anti-ROR1 CAR-T cells: architecture and performance[J]. Front Med (Lausanne), 2023, 10: 1121020.
49	LEE B K, WAN Y H, CHIN Z L, et al. Developing ROR1 targeting CAR-T cells against solid tumors in preclinical studies[J]. Cancers, 2022, 14(15): 3618.
50	SRIVASTAVA S, FURLAN S N, JAEGER-RUCKSTUHL C A, et al. Immunogenic chemotherapy enhances recruitment of CAR-T cells to lung tumors and improves antitumor efficacy when combined with checkpoint blockade[J]. Cancer Cell, 2021, 39(2): 193-208.e10.
51	JOSHI N, LIU D L, DICKSON K A, et al. An organotypic model of high-grade serous ovarian cancer to test the anti-metastatic potential of ROR2 targeted Polyion complex nanoparticles[J]. J Mater Chem B, 2021, 9(44): 9123-9135.
52	CHEN X Y, CHEN Y M, LIN X Y, et al. The drug combination of SB202190 and SP600125 significantly inhibit the growth and metastasis of olaparib-resistant ovarian cancer cell[J]. Curr Pharm Biotechnol, 2018, 19(6): 506-513.
53	OHTA T, TAKAHASHI T, SHIBUYA T, et al. Inhibition of the Rho/ROCK pathway enhances the efficacy of cisplatin through the blockage of hypoxia-inducible factor-1α in human ovarian cancer cells[J]. Cancer Biol Ther, 2012, 13(1): 25-33.

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