An Essential Role of the Cysteine-rich Domain of FZD4 in Norrin/Wnt Signaling and Familial Exudative Vitreoretinopathy

The Wnt pathway plays important yet diverse roles in health and disease. Mutations in the Wnt receptor FZD4 gene have been confirmed to cause familial exudative vitreoretinopathy (FEVR). FEVR is characterized by incomplete vascularization of the peripheral retina, which can lead to vitreous bleeding, tractional retinal detachment, and blindness. We screened for mutations in the FZD4 gene in five families with FEVR and identified five mutations (C45Y, Y58C, W226X, C204R, and W496X), including three novel mutations (C45Y, Y58C, and W226X). In the retina, Norrin serves as a ligand and binds to FZD4 to activate the Wnt signaling pathway in normal angiogenesis and vascularization. The cysteine-rich domain (CRD) of FZD4 has been shown to play a critical role in Norrin-FZD4 binding. We investigated the effect of mutations in the FZD4 CRD in Norrin binding and signaling in vitro and in vivo. Wild-type and mutant FZD4 proteins were assayed for Norrin binding and Norrin-dependent activation of the canonical Wnt pathway by cell-surface and overlay binding assays and luciferase reporter assays. In HEK293 transfection studies, C45Y, Y58C, and C204R mutants did not bind to Norrin and failed to transduce FZD4-mediated Wnt/β-catenin signaling. In vivo studies using Xenopus embryos showed that these FZD4 mutations disrupt Norrin/β-catenin signaling as evidenced by decreased Siamois and Xnr3 expression. This study identified a new class of FZD4 gene mutations in human disease and demonstrates a critical role of the CRD in Norrin binding and activation of the β-catenin pathway.

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Neddylation is critical to cortical development by regulating Wnt/β-catenin signaling

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2005395117 ◽

2020 ◽

Vol 117 (42) ◽

pp. 26448-26459 ◽

Cited By ~ 1

Author(s):

Lei Zhang ◽

Hongyang Jing ◽

Haiwen Li ◽

Wenbing Chen ◽

Bin Luo ◽

...

Keyword(s):

Wnt Signaling ◽

Protein Modification ◽

Radial Glia ◽

Critical Role ◽

Cortical Development ◽

Nuclear Accumulation ◽

Progressive Reduction ◽

Intermediate Progenitors

Wnt signaling plays a critical role in production and differentiation of neurons and undergoes a progressive reduction during cortical development. However, how Wnt signaling is regulated is not well understood. Here we provide evidence for an indispensable role of neddylation, a ubiquitylation-like protein modification, in inhibiting Wnt/β-catenin signaling. We show that β-catenin is neddylated; and inhibiting β-catenin neddylation increases its nuclear accumulation and Wnt/β-catenin signaling. To test this hypothesis in vivo, we mutated Nae1, an obligative subunit of the E1 for neddylation in cortical progenitors. The mutation leads to eventual reduction in radial glia progenitors (RGPs). Consequently, the production of intermediate progenitors (IPs) and neurons is reduced, and neuron migration is impaired, resulting in disorganization of the cerebral cortex. These phenotypes are similar to those of β-catenin gain-of-function mice. Finally, suppressing β-catenin expression is able to rescue deficits of Nae1 mutant mice. Together, these observations identified a mechanism to regulate Wnt/β-catenin signaling in cortical development.

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Impact and mechanistic role of MicroRNA-1291 on pancreatic tumorigenesis.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.243 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 243-243 ◽

Cited By ~ 1

Author(s):

Mei-Juan Tu ◽

Yu-Zhuo Pan ◽

Jing-Xin Qiu ◽

Edward Jae-hoon Kim ◽

Aiming Yu

Keyword(s):

Cell Cycle ◽

Cancer Biology ◽

Critical Role ◽

Experimental Studies ◽

Mass Spectrometry Analysis ◽

Ductal Adenocarcinoma ◽

Luciferase Reporter ◽

Spectrometry Analysis

243 Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death. Better understanding of pancreatic cancer biology and identification of new targets are highly warranted. MicroRNAs (miRs or miRNAs) play a critical role in the control of tumor progression via crosstalk with cancer signaling pathways. Our recent studies showed that miR-1291 improved chemosensitivity through targeting of efflux transporter ABCC1. This current study investigated the mechanistic role of miR-1291 in the suppression of pancreatic tumorigenesis. Methods: PANC-1 and AsPC-1 cell lines were stably transfected with miR-1291. Cell cycle status and apoptosis of stable miR-1291-expressing cells were tested against control cells using flow cytometry. Cells were injected subcutaneously into nude mice and tumorigenesis was measured in vivo. Proteomic studies were performed by two-dimensional difference gel electrophoresis, matrix-assisted laser desorption/ionization time of flight mass spectrometry analysis. Computationally predicted miR-1291 targets were assessed by luciferase reporter assay and Western blot. Primary PDAC and control samples were tested for miR-1291 and target gene expression levels. Results: Our data showed that stable miR-1291-expressing PANC-1 and AsPC-1 cells both showed a significantly lower rate of proliferation than the control cells, which was associated with a cell cycle arrest and enhanced apoptosis. Furthermore, miR-1291 suppressed the tumorigenesis of PANC-1 cells in mouse models in vivo. Proteomic studies revealed the protein level of several cancer-related genes were downregulated by miR-1291, including a pancreatic tumor promoting protein AGR2 which was reduced ~10-fold. Through computational and experimental studies we further identified that FOXA2, a transcription factor governing AGR2 expression, was a direct target of miR-1291. In addition, we found a significant down-regulation of miR-1291 in a set of PDAC patient tumor samples overexpressing AGR2. Conclusions: These results indicate that miR-1291 suppresses pancreatic tumorigenesis via targeting of FOXA2-AGR regulatory pathway providing new insight supporting development of miR-1291-based therapy for PDAC.

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KDM6A-ARHGDIB axis blocks metastasis of bladder cancer by inhibiting Rac1

Molecular Cancer ◽

10.1186/s12943-021-01369-9 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Lei Liu ◽

Jianfeng Cui ◽

Yajing Zhao ◽

Xiaochen Liu ◽

Lipeng Chen ◽

...

Keyword(s):

Bladder Cancer ◽

Cancer Progression ◽

Critical Role ◽

Metastatic Potential ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Tissue Specimens ◽

Invasion Assays

Abstract Background KDM6A, a histone demethylase, is frequently mutated in bladder cancer (BCa). However, the role and detailed molecular mechanism of KDM6A involved in bladder cancer progression remains unknown. Methods Tissue specimens were used to determine the expression levels and prognostic values of KDM6A and ARHGDIB. The MTT, colony formation, wound healing and Transwell migration and invasion assays were employed to detect the BCa cell proliferation, migration and invasion, respectively. Chemotaxis of macrophages was used to evaluate the ability of KDM6A to recruit macrophages. A subcutaneous tumour model and tail vein tumour injection in nude mice were used to assess the role of KDM6A in vivo. RNA sequencing, qPCR, Western blot, ChIP and phalloidin staining assay were performed to investigate the molecular functions of KDM6A. Dual-luciferase reporter assay was used to determine the effects of KDM6A and FOXA1 on the promoters of the ARHGDIB and KDM6A. Results We showed that the KDM6A inhibited the motility and invasiveness of the BCa cells. Mechanistically, KDM6A promotes the transcription of ARHGDIB by demethylating histone H3 lysine di/trimethylation (H3K27me2/3) and consequently leads to inhibition of Rac1. EZH2, which catalyses the methylation of H3K27, functions to silence ARHGDIB expression, and an EZH2 inhibitor can neutralize the metastatic effect caused by KDM6A deficiency. Furthermore, we demonstrated that FOXA1 directly binds to the KDM6A promoter and thus transactivates KDM6A, leading to diminished metastatic potential. Conclusion Our findings establish the critical role of the FOXA1-KDM6A-ARHGDIB axis in restraining the malignancy of BCa and identify KDM6A and EZH2 as potential therapeutic targets in the management of BCa.

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Deficient FGF signaling in the developing peripheral retina disrupts ciliary margin development and causes aniridia

10.1101/443416 ◽

2018 ◽

Author(s):

Revathi Balasubramanian ◽

Chenqi Tao ◽

Karina Polanco ◽

Jian Zhong ◽

Fen Wang ◽

...

Keyword(s):

Wnt Signaling ◽

Critical Role ◽

Peripheral Retina ◽

Fgf Signaling ◽

Surface Ectoderm ◽

Genetic Ablation ◽

Central Retina ◽

Ciliary Margin ◽

Wnt Ligands

ABSTRACTThe mammalian ciliary margin is a part of the developing peripheral neural retina that differentiates into the ciliary body and the iris. Canonical WNT signaling plays a critical role in the specification of the ciliary margin at the peripheral retina in the presence of strong FGF signaling in the central retina. The mechanism of how the boundary between the central retina and the ciliary margin is created has not been previously elucidated. Using genetic ablation and epistasis experiments, we show that loss of FGF signaling gradient in the peripheral retina causes expansion of WNT signaling towards the central retina thereby disrupting the neurogenic boundary and compartmentalization of the ciliary margin. Loss of WNT signaling displays a complimentary effect with expansion of FGF signaling into the ciliary marginal space. Using in vivo experiments, we elucidate the FGF signaling cascade involved in development of the ciliary margin. We also identify the surface ectoderm as the source of WNT ligands in eliciting WNT response at the ciliary margin. We show that an interaction between FGF and WNT signaling is required for generation of the ciliary marginal cells. Taken together, our results reveal that a gradient intersection of FGF and WNT signaling is required for specification of the ciliary margin.

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LncRNA CBR3-AS1 regulates of breast cancer drug sensitivity as a competing endogenous RNA through the JNK1/MEK4-mediated MAPK signal pathway

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01844-7 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Ming Zhang ◽

Yan Wang ◽

Longyang Jiang ◽

Xinyue Song ◽

Ang Zheng ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Critical Role ◽

Luciferase Reporter ◽

Cancer Drug ◽

Cancer Resistance ◽

Clinical Prognosis

Abstract Background Adriamycin (ADR) resistance is one of the main obstacles to improving the clinical prognosis of breast cancer patients. Long noncoding RNAs (lncRNAs) can regulate cell behavior, but the role of these RNAs in the anti-ADR activity of breast cancer remains unclear. Here, we aim to investigate the imbalance of a particular long noncoding RNA, lncRNA CBR3 antisense RNA 1 (CBR3-AS1), and its role in ADR resistance. Methods Microarray analysis of ADR-resistant breast cancer cells was performed to identify CBR3-AS1. CCK-8 and colony formation assays were used to detect the sensitivity of breast cancer cells to ADR. Dual-luciferase reporter, RNA pulldown, IHC and western blot analyses were used to verify the relationship between the expression of CBR3-AS1, miRNA and target genes. For in vivo experiments, the effect of CBR3-AS1 on breast cancer resistance was observed in a xenograft tumor model. The role of CBR3-AS1 in influencing ADR sensitivity was verified by clinical breast cancer specimens from the TCGA, CCLE, and GDSC databases. Results We found that CBR3-AS1 expression was significantly increased in breast cancer tissues and was closely correlated with poor prognosis. CBR3-AS1 overexpression promoted ADR resistance in breast cancer cells in vitro and in vivo. Mechanistically, we identified that CBR3-AS1 functioned as a competitive endogenous RNA by sponging miR-25-3p. MEK4 and JNK1 of the MAPK pathway were determined to be direct downstream proteins of the CBR3-AS1/miR-25-3p axis in breast cancer cells. Conclusions In summary, our findings demonstrate that CBR3-AS1 plays a critical role in the chemotherapy resistance of breast cancer by mediating the miR-25-3p and MEK4/JNK1 regulatory axes. The potential of CBR3-AS1 as a targetable oncogene and therapeutic biomarker of breast cancer was identified.

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miR-26a mediates LC-PUFA biosynthesis by targeting the Lxrα–Srebp1 pathway in the marine teleost Siganus canaliculatus

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.014858 ◽

2020 ◽

Vol 295 (40) ◽

pp. 13875-13886 ◽

Cited By ~ 1

Author(s):

Cuiying Chen ◽

Shuqi Wang ◽

Yu Hu ◽

Mei Zhang ◽

Xianda He ◽

...

Keyword(s):

Linolenic Acid ◽

Regulatory Element ◽

Critical Role ◽

Luciferase Reporter ◽

Chain Polyunsaturated Fatty Acid ◽

Siganus Canaliculatus ◽

Pufa Biosynthesis

MicroRNAs have been recently shown to be important regulators of lipid metabolism. However, the mechanisms of microRNA-mediated regulation of long-chain polyunsaturated fatty acid (LC-PUFA) biosynthesis in vertebrates remain largely unknown. Herein, we for the first time addressed the role of miR-26a in LC-PUFA biosynthesis in the marine rabbitfish Siganus canaliculatus. The results showed that miR-26a was significantly down-regulated in liver of rabbitfish reared in brackish water and in S. canaliculatus hepatocyte line (SCHL) incubated with the LC-PUFA precursor α-linolenic acid, suggesting that miR-26a may be involved in LC-PUFA biosynthesis because of its abundance being regulated by factors affecting LC-PUFA biosynthesis. Opposite patterns were observed in the expression of liver X receptor α (lxrα) and sterol regulatory element-binding protein-1 (srebp1), as well as the LC-PUFA biosynthesis–related genes (Δ4 fads2, Δ6Δ5 fads2, and elovl5) in SCHL cells incubated with α-linolenic acid. Luciferase reporter assays revealed rabbitfish lxrα as a target of miR-26a, and overexpression of miR-26a in SCHL cells markedly reduced protein levels of Lxrα, Srebp1, and Δ6Δ5 Fads2 induced by the agonist T0901317. Moreover, increasing endogenous Lxrα by knockdown of miR-26a facilitated Srebp1 activation and concomitant increased expression of genes involved in LC-PUFA biosynthesis and consequently promoted LC-PUFA biosynthesis both in vitro and in vivo. These results indicate a critical role of miR-26a in regulating LC-PUFA biosynthesis through targeting the Lxrα–Srebp1 pathway and provide new insights into the regulatory network controlling LC-PUFA biosynthesis and accumulation in vertebrates.

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Molecular Role of RNF43 in Canonical and Noncanonical Wnt Signaling

Molecular and Cellular Biology ◽

10.1128/mcb.00159-15 ◽

2015 ◽

Vol 35 (11) ◽

pp. 2007-2023 ◽

Cited By ~ 33

Author(s):

Tadasuke Tsukiyama ◽

Akimasa Fukui ◽

Sayuri Terai ◽

Yoichiro Fujioka ◽

Keisuke Shinada ◽

...

Keyword(s):

Wnt Signaling ◽

Target Genes ◽

Pdz Domain ◽

Ring Finger ◽

Missense Mutations ◽

Ring Finger Domain ◽

Rich Domain ◽

Insight Into ◽

Cysteine Rich Domain

Wnt signaling pathways are tightly regulated by ubiquitination, and dysregulation of these pathways promotes tumorigenesis. It has been reported that the ubiquitin ligase RNF43 plays an important role in frizzled-dependent regulation of the Wnt/β-catenin pathway. Here, we show that RNF43 suppresses both Wnt/β-catenin signaling and noncanonical Wnt signaling by distinct mechanisms. The suppression of Wnt/β-catenin signaling requires interaction between the extracellular protease-associated (PA) domain and the cysteine-rich domain (CRD) of frizzled and the intracellular RING finger domain of RNF43. In contrast, these N-terminal domains of RNF43 are not required for inhibition of noncanonical Wnt signaling, but interaction between the C-terminal cytoplasmic region of RNF43 and the PDZ domain of dishevelled is essential for this suppression. We further show the mechanism by which missense mutations in the extracellular portion of RNF43 identified in patients with tumors activate Wnt/β-catenin signaling. Missense mutations of RNF43 change their localization from the endosome to the endoplasmic reticulum (ER), resulting in the failure of frizzled-dependent suppression of Wnt/β-catenin signaling. However, these mutants retain the ability to suppress noncanonical Wnt signaling, probably due to interaction with dishevelled. RNF43 is also one of the potential target genes of Wnt/β-catenin signaling. Our results reveal the molecular role of RNF43 and provide an insight into tumorigenesis.

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LncRNA CBR3-AS1 regulates of breast cancer drug sensitivity as a competing endogenous RNA through the JNK1/MEK4‑mediated MAPK signal pathway

10.21203/rs.3.rs-54834/v2 ◽

2021 ◽

Author(s):

Ming Zhang ◽

Yan Wang ◽

Longyang Jiang ◽

Xinyue Song ◽

Ang Zheng ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Critical Role ◽

Luciferase Reporter ◽

Cancer Drug ◽

Cancer Resistance ◽

Clinical Prognosis

Abstract Background: Adriamycin (ADR) resistance is one of the main obstacles to improving the clinical prognosis of breast cancer patients. Long noncoding RNAs (lncRNAs) can regulate cell behavior, but the role of these RNAs in the anti-ADR activity of breast cancer remains unclear. Here, we aim to investigate the imbalance of a particular long noncoding RNA, lncRNA CBR3 antisense RNA 1 (CBR3-AS1), and its role in ADR resistance.Methods: Microarray analysis of ADR-resistant breast cancer cells was performed to identify CBR3-AS1. CCK-8 and colony formation assays were used to detect the sensitivity of breast cancer cells to ADR. Dual-luciferase reporter, RNA pulldown, IHC and western blot analyses were used to verify the relationship between the expression of CBR3-AS1, miRNA and target genes. For in vivo experiments, the effect of CBR3-AS1 on breast cancer resistance was observed in a xenograft tumor model. The role of CBR3-AS1 in influencing ADR sensitivity was verified by clinical breast cancer specimens from the TCGA, CCLE, and GDSC databases.Results: We found that CBR3-AS1 expression was significantly increased in breast cancer tissues and was closely correlated with poor prognosis. CBR3-AS1 overexpression promoted ADR resistance in breast cancer cells in vitro and in vivo. Mechanistically, we identified that CBR3-AS1 functioned as a competitive endogenous RNA by sponging miR-25-3p. MEK4 and JNK1 of the MAPK pathway were determined to be direct downstream proteins of the CBR3-AS1/miR-25-3p axis in breast cancer cells.Conclusions: In summary, our findings demonstrate that CBR3-AS1 plays a critical role in the chemotherapy resistance of breast cancer by mediating the miR-25-3p and MEK4/JNK1 regulatory axes. The potential of CBR3-AS1 as a targetable oncogene and therapeutic biomarker of breast cancer was identified.

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A novel protein AXIN1-295aa encoded by circAXIN1 activates the Wnt/β-catenin signaling pathway to promote gastric cancer progression

Molecular Cancer ◽

10.1186/s12943-021-01457-w ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Yin Peng ◽

Yidan Xu ◽

Xiaojing Zhang ◽

Shiqi Deng ◽

Yuan Yuan ◽

...

Keyword(s):

Gastric Cancer ◽

Wnt Signaling ◽

Signaling Pathway ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Coding Potential ◽

Novel Protein

Abstract Background Circular RNA (circRNA), a subclass of non-coding RNA, plays a critical role in cancer tumorigenesis and metastasis. It has been suggested that circRNA acts as a microRNA sponge or a scaffold to interact with protein complexes; however, its full range of functions remains elusive. Recently, some circRNAs have been found to have coding potential. Methods To investigate the role of circRNAs in gastric cancer (GC), parallel sequencing was performed using five paired GC samples. Differentially expressed circAXIN1 was proposed to encode a novel protein. FLAG-tagged circRNA overexpression plasmid construction, immunoblotting, mass spectrometry, and luciferase reporter analyses were applied to confirm the coding potential of circAXIN1. Gain- and loss-of-function studies were conducted to study the oncogenic role of circAXIN1 and AXIN1-295aa on the proliferation, migration, invasion, and metastasis of GC cells in vitro and in vivo. The competitive interaction between AXIN1-295aa and adenomatous polyposis coli (APC) was investigated by immunoprecipitation analyses. Wnt signaling activity was observed using a Top/Fopflash assay, real-time quantitative RT-PCR, immunoblotting, immunofluorescence staining, and chromatin immunoprecipitation. Results CircAXIN1 is highly expressed in GC tissues compared with its expression in paired adjacent normal gastric tissues. CircAXIN1 encodes a 295 amino acid (aa) novel protein, which was named AXIN1-295aa. CircAXIN1 overexpression enhances the cell proliferation, migration, and invasion of GC cells, while the knockdown of circAXIN1 inhibits the malignant behaviors of GC cells in vitro and in vivo. Mechanistically, AXIN1-295aa competitively interacts with APC, leading to dysfunction of the “destruction complex” of the Wnt pathway. Released β-catenin translocates to the nucleus and binds to the TCF consensus site on the promoter, inducing downstream gene expression. Conclusion CircAXIN1 encodes a novel protein, AXIN1-295aa. AXIN1-295aa functions as an oncogenic protein, activating the Wnt signaling pathway to promote GC tumorigenesis and progression, suggesting a potential therapeutic target for GC.

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The BCL9 Oncogene Promotes Tumor Progression by Conferring Enhanced Proliferative, Metastatic and Angiogenic Properties to Myeloma Cells

Blood ◽

10.1182/blood.v112.11.648.648 ◽

2008 ◽

Vol 112 (11) ◽

pp. 648-648

Author(s):

Mala Mani ◽

Jui Dutta ◽

Yunyu Zhang ◽

Daniel E Carrasco ◽

Yiming Zhou ◽

...

Keyword(s):

Wnt Signaling ◽

Tumor Progression ◽

Cyclin D1 ◽

Wnt Pathway ◽

Target Genes ◽

Metastatic Potential ◽

Luciferase Reporter ◽

Aberrant Expression

Abstract Wnt signaling plays an important role in tissue development and maintenance during embryogenesis, cell differentiation, and stem cell growth. Several components of the Wnt signaling cascade have been shown to function as either tumor suppressor proteins or as oncogenes in multiple human cancers, underscoring the relevance of this pathway in oncogenesis. Deregulation of the canonical Wnt/b-catenin pathway has been implicated in numerous human epithelial malignancies as well as hematologic malignancies including multiple myeloma (MM), generating immense interest in these molecules as targets for cancer therapy. Activation of Wnt/b-catenin in cancer has been associated with mutations that enable b-catenin to escape degradation by the proteasome, thereby allowing its accumulation in the nucleus where it functions as a transcriptional regulator in conjunction with coactivators by constitutively activating target genes such as c-Myc and Cyclin D1. To date, however, no mutations in Wnt pathway have been documented in MM, suggesting that mechanisms other than gene mutation may contribute to Wnt pathway deregulation. BCL9, a key component of the Wnt pathway, is required for b-catenin transcriptional activity and resides on chromosome 1q21, a region frequently involved in secondary chromosomal aberrations associated with MM tumor progression. Here we provide evidence that dysregulation of BCL9 expression is a novel oncogenic mechanism of Wnt pathway activation in MM. Using in vitro and in vivo functional analyses, we demonstrate that BCL9 is a bonafide oncogene that is aberrantly expressed in MM and associated with survival. Using the TCF- specific luciferase reporter, we show that enforced expression of BCL9 in MM cells enhanced b-catenin mediated transcription by >12 fold, suggesting a possible role of BCL9 overexpression in the pathogenesis of MM. BCL9 enhanced proliferation (1.5 fold, P<0.02), migration (3.5 fold, P<0.0001) and the metastatic potential of MM cells. We also showed that BCL9 plays an important role in tumor progression by regulating Cyclin D1 and c-Myc mediated cell proliferation, CD44 mediated tumor metastasis, as well as VEGF mediated host angiogenesis. Importantly, BCL9 knockdown significantly increased the survival in a xenograft mouse model of human MM (P=0.001), associated with decreased tumor burden and host angiogenesis. In summary, we have demonstrated that BCL9 is a novel and potent oncogene of the Wnt pathway in MM, playing fundamental roles in tumor progression by regulating proliferation, migration, invasion, angiogenesis and the metastatic potential of tumor cells. The pleiotropic roles of BCL9 and its aberrant expression highlight its importance as an attractive and novel therapeutic target in the treatment of MM.

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