FKBP3 aggravates the malignant phenotype of diffuse large B-cell lymphoma by PARK7-mediated activation of Wnt/ß-catenin signalling.

Diffuse large B-cell lymphoma (DLBCL) is difficult to treat due to the high recurrence rate and therapy intolerance, so finding potential therapeutic targets for DLBCL is critical. FK506-binding protein 3 (FKBP3) contributes to the progression of various cancers and is highly expressed in DLBCL, but the role of FKBP3 in DLBCL and its mechanism are not clear. Our study demonstrated that FKBP3 aggravated the proliferation and stemness of DLBCL cells, and tumour growth in a xenograft mouse model. The interaction between FKBP3 and parkinsonism associated deglycase (PARK7) in DB cells was found using co-immunoprecipitation assay. Knockdown of FKBP3 enhanced the degradation of PARK7 through increasing its ubiquitination modification. Forkhead Box O3 (FOXO3) belongs to the forkhead family of transcription factors and inhibits DLBCL, but the underlying mechanism has not been reported. We found that FOXO3 bound the promoter of FKBP3 and then suppressed its transcription, eventually weakening DLBCL. Mechanically, FKBP3 activated Wnt/ß-catenin signalling pathway mediated by PARK7. Together, FKBP3 increased PARK7 and then facilitated the malignant phenotype of DLBCL through activating Wnt/ß-catenin pathway. These results indicated that FKBP3 might be a potential therapeutic target for the treatment of DLBCL.

Ras interacting protein 1 facilitated proliferation and invasion of diffuse large B-cell lymphoma cells.

A GTPase binding protein, Ras interacting protein 1 (RASIP1), has been reported with a tumor-promoting role in lung cancer cells, and its role in lymphoma remains unknown. The analysis of medical databank shows that RASIP1 is upregulated in diffuse large B-cell lymphoma (DLBCL) specimens. In this article, we demonstrated that RASIP1 is highly expressed in DLBCL cell lines, compared with primary B cells. The gain- and loss-of-function experiments were performed to investigate the effects of RASIP1 on DLBCL cells. CCK-8, flow cytometry, western blot, and transwell assays demonstrated that silence of RASIP1 inhibited proliferation, cell cycle transition, and invasion and induced significant apoptosis in DLBCL cells, and ectopic expression of RASIP1 played opposite roles. Xenograft results revealed that RASIP1 facilitated the growth of DLBCL cells in vivo. These findings suggest that RASIP1 may be required for malignancy of DLBCL cells. In addition, we also found that the expression of RASIP1 was negatively regulated by forkhead box O3 (FOXO3), which has been reported to suppress the proliferation of DLBCL cells. Our results indicate that FOXO3 is bound to the promoter sequence of RASIP1 and inhibits its transcription. The suppressive effects of FOXO3 on proliferation and invasion of DLBCL cells were neutralized by RASIP1. In conclusion, we demonstrate that FOXO3 negatively regulated RASIP1 facilitates growth and invasion of DLBCL cells, provides novel diagnostic markers and therapeutic targets for DLBCL in clinic.

Promoting effects of calponin 3 on the growth of diffuse large B­cell lymphoma cells.

Diffuse large B­cell lymphoma (DLBCL) is one of the most common types of lymphoma. Calponin 3 (CNN3) is a thin filament­associated protein previously known to regulate smooth muscle contraction. Recent evidence illustrates its involvement in carcinogenesis; however, its roles in DLBCL remain unknown. CNN3 was found to be highly expressed in DLBCL specimens according to the online Gene Expression Profiling Interactive Analysis data. The aim of the present study was to investigate the roles of CNN3 in the progression of DLBCL. In vitro, the ectopic expression of CNN3 promoted the proliferation and G1/S transition of DLBCL cells, while its silencing led to opposite alterations. A similar tumor­promoting role of CNN3 was also demonstrated by injecting nude mice with DLBCL cells over­ or underexpressing CNN3. The results of dual­luciferase reporter and chromatin immunoprecipitation assays revealed that forkhead box O3 (FOXO3), a known tumor suppressor in DLBCL, bound to the CNN3 promoter at ­1955/­1948 and ­1190/­1183, and suppressed the transcription of CNN3. The alterations induced by FOXO3 were partly blocked by CNN3 overexpression. On the whole, the present study demonstrates that CNN3, whose transcriptional activity is negatively regulated by FOXO3, contributes to the malignant behavior of DLBCL cells. The findings of the present study may provide novel diagnostic or therapeutic insight for DLBCL in clinical practice.

LncRNA SNHG5 can Regulate the Proliferation and Migration of Diffuse Large B Cell Lymphoma Progression via Targeting miR-181-5p/XIAP.

Background: It has been verified that long noncoding RNAs (lncRNAs) may participate in the pathogenesis of various human diseases. This study aims to investigate the roles of lncRNA SNHG5 in diffuse large B cell lymphoma (DLBC), especially the impacts of lncRNA SNHG5 on proliferation and migration of human diffuse large B cell lymphoma cells and the related mechanism. Methods: qRT-PCR analysis was carried out to examine the expression pattern of SNHG5 in DLBC tissue and adjacent normal tissue. The effect of SNHG5 on the proliferation, apoptosis, migration, and invasion of DLBC cells was detected by MTT, flow cytometry analysis, wound healing assay and transwell assay. The correlation between SNHG5, miR-181-5p and XIAP were certified by bioinformatics analysis, and dual-luciferase reporter assay. Furthermore, rescue assays were performed to analyze the effects of SNHG5-miR-181-5p-XIAP axis on the biological behaviors of diffuse large B cell lymphoma cells. Finally, the effects of SNHG5 axis on the growth of DLBC tumor was examined by in vivo analysis. Results: SNHG5 was significantly upregulated in diffuse large B cell lymphoma tissues. Knockdown of SNHG5 inhibited the proliferation, migration, and invasion of diffuse large B cell lymphoma cells in vitro and in vivo. LncRNA SNHG5 acted as a ceRNA through binding with miR-181-5p in DLBC cells. Conclusion: LncRNA SNHG5 may promote proliferation and migration of diffuse large B cell lymphoma cells via targeting miR-181-5p/XIAP.

ZNF259 promotes breast cancer cells invasion and migration via ERK/GSK3ß/snail signaling.

PURPOSE: Zinc finger protein 259 (ZNF259), also known as ZPR1, is a zinc finger-containing protein that can bind the intracellular tyrosine kinase domain of EGFR. At present, our knowledge on ZNF259 in cancers is limited. Here, we aimed to explore the biological functions of ZNF259 in breast cancer and reveal their mechanisms. PATIENTS AND METHODS: The expression of ZNF259 was measured in 133 cases of breast cancer by immunohistochemistry. The online database Kaplan-Meier (KM) Plotter Online Tool was used to analyze the relationship between ZNF259 expression and breast cancer patient survival prognosis. Plasmid transfection and small interfering RNA and inhibitor treatments were carried out to explore the functions of ZNF259 in breast cancer cell lines and its potential mechanism. Matrigel invasion and wound healing assays were performed to detect the invasion and migration ability of cancer cells. In addition, protein expressions in tissues and cells were determined by Western blotting. RESULTS: ZNF259 expression was much higher in breast cancer cells than in the adjacent normal breast duct glandular epithelial cells (75.94% vs 7.52%, P<0.001) and was closely related to the breast cancer patients' TNM stages (P=0.013) and lymph node metastasis (P=0.021). Knockdown of ZNF259 could downregulate p-ERK, p-GSK3ß, and Snail expression, and upregulate the expression of E-cadherin and ZO-1, and then it also inhibited invasion and migration by the breast cancer cell lines MCF-7 and MDA-MB-231. Correspondingly, ZNF259 transfection could upregulate p-ERK, p-GSK3ß, and Snail expression, and downregulate E-cadherin and ZO-1 expression, which led to stronger invasion and migration abilities of cancer cells. Furthermore, the ERK inhibitor U0126 could reverse all these effects induced by ZNF259 transfection. CONCLUSION: ZNF259 could promote breast cancer cell invasion and migration by activating the ERK/GSK3ß/Snail signaling pathway.