Frizzled-7-targeting antibody (SHH002-hu1) potently suppresses non-small-cell lung cancer via Wnt/β-catenin signaling.

Non-small-cell lung cancer (NSCLC) is one of the deadliest cancers worldwide, and metastasis is considered one of the leading causes of treatment failure in NSCLC. Wnt/β-catenin signaling is crucially involved in epithelial-mesenchymal transition (EMT), a crucial factor in promoting metastasis, and also contributes to resistance developed by NSCLC to targeted agents. Frizzled-7 (Fzd7), a critical receptor of Wnt/β-catenin signaling, is aberrantly expressed in NSCLC and has been confirmed to be positively correlated with poor clinical outcomes. SHH002-hu1, a humanized antibody targeting Fzd7, was previously successfully generated by our group. Here, we studied the anti-tumor effects of SHH002-hu1 against NSCLC and revealed the underlying mechanism. First, immunofluorescence (IF) and near-infrared (NIR) imaging assays showed that SHH002-hu1 specifically binds Fzd7+ NSCLC cells and targets NSCLC tissues. Wound healing and transwell invasion assays indicated that SHH002-hu1 significantly inhibits the migration and invasion of NSCLC cells. Subsequently, TOP-FLASH/FOP-FLASH luciferase reporter, IF, and western blot assays validated that SHH002-hu1 effectively suppresses the activation of Wnt/β-catenin signaling, and further attenuates the EMT of NSCLC cells. Finally, the subcutaneous xenotransplanted tumor model of A549/H1975, as well as the popliteal lymph node (LN) metastasis model, was established, and SHH002-hu1 was demonstrated to inhibit the growth of NSCLC xenografts and suppress LN metastasis of NSCLC. Above all, SHH002-hu1 with selectivity toward Fzd7+ NSCLC and the potential of inhibiting invasion and metastasis of NSCLC via disrupting Wnt/β-catenin signaling, is indicated as a good candidate for the targeted therapy of NSCLC.

Li K ，Mao S ，Li X ，Zhao H ，Wang J ，Wang C ，Wu L ，Zhang K ，Yang H ，Jin M ，Zhou Z ，Wang J ，Huang G ，Xie W ... -  《-》

A novel humanized Frizzled-7-targeting antibody enhances antitumor effects of Bevacizumab against triple-negative breast cancer via blocking Wnt/β-catenin signaling pathway.

Xie W ，Zhao H ，Wang F ，Wang Y ，He Y ，Wang T ，Zhang K ，Yang H ，Zhou Z ，Shi H ，Wang J ，Huang G ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》

Downregulation of miR-3127-5p promotes epithelial-mesenchymal transition via FZD4 regulation of Wnt/β-catenin signaling in non-small-cell lung cancer.

MiR-3127-5p has been implicated as a tumor-suppressive microRNA (miRNA) in non-small-cell lung cancer (NSCLC) and its expression was associated with tumor recurrence and poor prognosis. The aim of this study was to determine whether miR-3127-5p regulates epithelial-mesenchymal transition (EMT) in NSCLC, and to investigate the underlying mechanisms. Using qRT-PCR, we examined the expression levels of miR-3127-5p in a cohort of primary NSCLC specimens with and without distant metastasis. We further performed a series of in vitro and in vivo experiments to investigate the effects and underlying mechanism of miR-3127-5p on EMT, cell migration, invasion, and adhesion in NSCLC. We found that metastatic NSCLC tissues showed markedly downregulated miR-3127-5p expression. Transforming growth factor-β1 (TGF-β1) treatment induced EMT in A549 and H1299 cells, and downregulation of miR-3127-5p could result in the similar effect. Mechanically, we demonstrated that frizzled-4 (FZD4) is a target gene and miR-3127-5p exerts its effects by regulating the Wnt/β-catenin signaling. In addition, the expression levels of FZD4 and miR-3127-5p were also negatively associated in both clinical and xenografted tumors. Overall, these findings suggest that downregulation of miR-3127-5p promotes EMT through activating the Wnt/FZD4/β-catenin signaling pathway and may represent a therapeutic target for NSCLC metastasis.

Yang Y ，Sun Y ，Wu Y ，Tang D ，Ding X ，Xu W ，Su B ，Gao W ... -  《-》

miR-504 suppresses mesenchymal phenotype of glioblastoma by directly targeting the FZD7-mediated Wnt-β-catenin pathway.

Liu Q ，Guan Y ，Li Z ，Wang Y ，Liu Y ，Cui R ，Wang Y ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》

BCL9 promotes epithelial mesenchymal transition and invasion in cisplatin resistant NSCLC cells via β-catenin pathway.

Bcell lymphoma 9 (BCL9)-Wnt/β-catenin pathway, a key signaling pathway related to epithelial-mesenchymal transition (EMT), is widely considered to be involved in invasion in various malignant tumors. However, the dysregulation of BCL9/β-catenin pathway in non-small cell lung cancer (NSCLC) has not been revealed. This study aimed to investigate the correlation between chemotherapy resistance and BCL9/Wnt/β-catenin signaling dysfunction. We performed BCL9 knockdown using a lentivirus-mediated sh-RNA interference in cisplatin-resistant (CR) lung cancer cells. Subsequently, the migration and invasion were determined by wound-healing and Transwell assays. Furthermore, EMT markers and β-catenin were examined by Western blot. Immunofluorescence was used to investigate the subcellular localization of β-catenin. The chemotherapeutic sensitivity to cisplatin in A549/DDP cell lines after treatment with BCL9 sh-RNA was estimated by MTT assay. The knockdown of BCL9 remarkably reduced the migration and invasion abilities of A549/DDP cells. Meanwhile, nuclear translocation of β-catenin was reduced after BCL9 was knocked down. BCL9 silencing also resulted in the downregulation of EMT-related proteins. Additionally, the Wnt/β-catenin agonist, CP21, significantly restored the expression of β-catenin and abilities of migration and invasion in BCL9-knockdown A549/DDP cell lines. Finally, we proved that the inhibition of BCL9 could partially attenuate the stemness of cancer cells and recover the chemotherapeutic sensitivity. These findings indicated BCL9 induced the occurrence of EMT and enhancement of stemness, which resulted in cisplatin-resistance and promoted migration in NSCLC cells. Mechanically, Wnt/β-catenin pathway is crucial in BCL9-induced migration, invasion, and chemotherapy resistance.

Zhang Y ，Zhang Q ，Chen H ，Wang C ... -  《-》