Molecular genetics and targeted therapy of WNT-related human diseases (Review).
Molecular genetics and targeted therapy of WNT-related human diseases (Review).
复制标题
DOI：
10.3892/ijmm.2017.3071
复制
发表时间：
2017-09
影响因子：
5.4
通讯作者：
Katoh M
中科院分区：
文献类型：
--
作者：
Katoh M;Katoh M
通过Frizzled和LRP 5/6受体的典型WNT信号转导被转导至WNT/β-连环蛋白和WNT/蛋白质稳定化（STOP）信号转导级联以调节细胞命运和增殖，而通过Frizzled或ROR受体的非典型WNT信号转导被转导至WNT/平面细胞极性（PCP），WNT/G蛋白偶联受体（GPCR）和WNT/受体酪氨酸激酶（RTK）信号级联调节细胞骨架动力学和定向细胞运动。WNT/β-catenin信号级联与RTK/SRK和GPCR-cAMP-PKA信号级联串扰以调节β-catenin磷酸化和β-catenin依赖性转录。WNT信号分子的种系突变可导致遗传性结直肠癌、骨疾病、渗出性玻璃体视网膜病变、智力残疾综合征和PCP相关疾病。结直肠癌、子宫内膜癌和前列腺癌中的APC或CTNNB 1突变激活WNT/β-catenin信号级联。乳腺癌、结肠直肠癌、胃癌、胰腺癌和其他癌症中的RNF 43、ZNRF 3、RSPO 2或RSPO 3改变激活WNT/β-连环蛋白、WNT/STOP和其他WNT信号级联。B细胞白血病和实体瘤中的ROR 1上调和黑色素瘤中的ROR 2上调通过Rho-ROCK、Rac-JNK、PI 3 K-AKT和雅普信号传导激活诱导侵袭、转移和治疗抗性。癌症、基质细胞和免疫细胞中的WNT信号传导以细胞环境依赖性方式动态地协调免疫逃避和抗肿瘤免疫。豪猪（PORCN）、RSPO 3、WNT 2B、FZD 5、FZD 10、ROR 1、端锚聚合酶和β-连环蛋白是抗WNT信号疗法的靶点，ETC-159、LGK 974、OMP-18 R5（vantictumab）、OMP-54 F28（ipafricept）、OMP-131 R10（rosmantuzumab）、PRI-724和UC-961（cirmtuzumab）正在对癌症患者进行临床试验。不同种类的抗WNT信号传导治疗剂对于治疗APC/CTNNB 1-、RNF 43/ZNRF 3/RSPO 2/RSPO 3-和ROR 1-类型的人类癌症是必需的。相比之下，Dickkopf相关蛋白1（DKK 1）、SOST和糖原合成酶激酶3β（GSK 3 β）是pro-WNT信号疗法的靶点，抗DKK 1（BHQ 880和DKN-01）和抗SOST（blosozumab、BPS 804和romosozumab）单克隆抗体正在癌症患者和绝经后妇女的临床试验中进行测试。WNT靶向治疗剂也已在再生医学领域中用作体外干细胞处理的试剂。
Canonical WNT signaling through Frizzled and LRP5/6 receptors is transduced to the WNT/β-catenin and WNT/stabilization of proteins (STOP) signaling cascades to regulate cell fate and proliferation, whereas non-canonical WNT signaling through Frizzled or ROR receptors is transduced to the WNT/planar cell polarity (PCP), WNT/G protein-coupled receptor (GPCR) and WNT/receptor tyrosine kinase (RTK) signaling cascades to regulate cytoskeletal dynamics and directional cell movement. WNT/β-catenin signaling cascade crosstalks with RTK/SRK and GPCR-cAMP-PKA signaling cascades to regulate β-catenin phosphorylation and β-catenin-dependent transcription. Germline mutations in WNT signaling molecules cause hereditary colorectal cancer, bone diseases, exudative vitreoretinopathy, intellectual disability syndrome and PCP-related diseases. APC or CTNNB1 mutations in colorectal, endometrial and prostate cancers activate the WNT/β-catenin signaling cascade. RNF43, ZNRF3, RSPO2 or RSPO3 alterations in breast, colorectal, gastric, pancreatic and other cancers activate the WNT/β-catenin, WNT/STOP and other WNT signaling cascades. ROR1 upregulation in B-cell leukemia and solid tumors and ROR2 upregulation in melanoma induce invasion, metastasis and therapeutic resistance through Rho-ROCK, Rac-JNK, PI3K-AKT and YAP signaling activation. WNT signaling in cancer, stromal and immune cells dynamically orchestrate immune evasion and antitumor immunity in a cell context-dependent manner. Porcupine (PORCN), RSPO3, WNT2B, FZD5, FZD10, ROR1, tankyrase and β-catenin are targets of anti-WNT signaling therapy, and ETC-159, LGK974, OMP-18R5 (vantictumab), OMP-54F28 (ipafricept), OMP-131R10 (rosmantuzumab), PRI-724 and UC-961 (cirmtuzumab) are in clinical trials for cancer patients. Different classes of anti-WNT signaling therapeutics are necessary for the treatment of APC/CTNNB1-, RNF43/ZNRF3/RSPO2/RSPO3- and ROR1-types of human cancers. By contrast, Dickkopf-related protein 1 (DKK1), SOST and glycogen synthase kinase 3β (GSK3β) are targets of pro-WNT signaling therapy, and anti-DKK1 (BHQ880 and DKN-01) and anti-SOST (blosozumab, BPS804 and romosozumab) monoclonal antibodies are being tested in clinical trials for cancer patients and osteoporotic post-menopausal women. WNT-targeting therapeutics have also been applied as reagents for in vitro stem-cell processing in the field of regenerative medicine.
登录
查看更多内容
影响因子：
8.3
作者：
Arabzadeh S;Hossein G;Salehi-Dulabi Z;Zarnani AH
通讯作者：
Zarnani AH
影响因子：
3.7
作者：
Bozdag S;Li A;Riddick G;Kotliarov Y;Baysan M;Iwamoto FM;Cam MC;Kotliarova S;Fine HA
通讯作者：
Fine HA
影响因子：
11.8
作者：
Birdsey, Graeme M.;Shah, Aarti V.;Dufton, Neil;Reynolds, Louise E.;Almagro, Lourdes Osuna;Yang, Youwen;Aspalter, Irene M.;Khan, Samia T.;Mason, Justin C.;Dejana, Elisabetta;Goettgens, Berthold;Hodivala-Dilke, Kairbaan;Gerhardt, Holger;Adams, Ralf H.;Randi, Anna M.
通讯作者：
Randi, Anna M.
影响因子：
158.5
作者：
Biason-Lauber, A;Konrad, D;Schoenle, EJ
通讯作者：
Schoenle, EJ
影响因子：
30.8
作者：
Afzal, AR;Rajab, A;Jeffery, S
通讯作者：
Jeffery, S