Role of deubiquitinase JOSD2 in the pathogenesis of esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a deadly malignancy with limited treatment options. Deubiquitinases (DUBs) have been confirmed to play a crucial role in the development of malignant tumors. JOSD2 is a DUB involved in controlling protein deubiquitination and influencing critical cellular processes in cancer. AIM: To investigate the impact of JOSD2 on the progression of ESCC. METHODS: Bioinformatic analyses were employed to explore the expression, prognosis, and enriched pathways associated with JOSD2 in ESCC. Lentiviral transduction was utilized to manipulate JOSD2 expression in ESCC cell lines (KYSE30 and KYSE150). Functional assays, including cell proliferation, colony formation, drug sensitivity, migration, and invasion, were performed, revealing the impact of JOSD2 on ESCC cell lines. JOSD2's role in xenograft tumor growth and drug sensitivity in vivo was also assessed. The proteins that interacted with JOSD2 were identified using mass spectrometry. RESULTS: Preliminary research indicated that JOSD2 was highly expressed in ESCC tissues, which was associated with poor prognosis. Further analysis demonstrated that JOSD2 was upregulated in ESCC cell lines compared to normal esophageal cells. JOSD2 knockdown inhibited ESCC cell activity, including proliferation and colony-forming ability. Moreover, JOSD2 knockdown decreased the drug resistance and migration of ESCC cells, while JOSD2 overexpression enhanced these phenotypes. In vivo xenograft assays further confirmed that JOSD2 promoted tumor proliferation and drug resistance in ESCC. Mechanistically, JOSD2 appears to activate the MAPK/ERK and PI3K/AKT signaling pathways. Mass spectrometry was used to identify crucial substrate proteins that interact with JOSD2, which identified the four primary proteins that bind to JOSD2, namely USP47, IGKV2D-29, HSP90AB1, and PRMT5. CONCLUSION: JOSD2 plays a crucial role in enhancing the proliferation, migration, and drug resistance of ESCC, suggesting that JOSD2 is a potential therapeutic target in ESCC.

Prognosis model of colorectal cancer patients based on NOTCH3, KMT2C, and CREBBP mutations.

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers. The aim of our study was to explore its related mutations, identify novel mutation markers, and construct predictive models for postoperative CRC patients, so as to provide evidence for the diagnosis, treatment, and prognosis of CRC. METHODS: A total 50 CRC patients were collected, and the mutations in tissue samples were detected through next-generation sequencing (NGS). Meanwhile, 246 CRC cases with complete mutation data were downloaded from The Cancer Genome Atlas (TCGA) database. Afterwards, the co-mutations in both clinical and TCGA cohorts were identified, and the high-frequency mutation genes were selected. Subsequently, functional enrichment analysis was performed, and overall survival (OS) and progression-free survival (PFS) predictive models were constructed. RESULTS: In all, 18 out of 238 co-mutation genes mutated in at least 20% of the samples and were selected out as common high-frequency mutation genes. They were significantly enriched in 460 Gene Ontology (GO) terms and 87 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways (P<0.05), which were closely related to the occurrence and development of CRC. Among the 18 genes, NOTCH3, histone lysine methyltransferase 2C (KMT2C), and cAMP-response element binding protein-BP (CREBBP) were respectively associated with tumor position, stage, and PFS (P<0.05), and could be considered as potential biomarkers of CRC. Finally, OS and PFS predictive models were constructed and verified using the 50 clinical cases, with both models demonstrating high fitting degrees useful for predicting the OS and PFS of CRC patients. CONCLUSIONS: NOTCH3, KMT2C, and CREBBP were found to be prospective biomarkers for the diagnosis and prognosis of CRC. The prognosis prediction models had high sensitivity and could be used to predict the OS and PFS of CRC patients.

SP1-mediated microRNA-520d-5p suppresses tumor growth and metastasis in colorectal cancer by targeting CTHRC1.

Recent evidence suggests that miR-520 family has an important role in regulating tumorigenesis and development of various types of solid cancers. However, as one of the most common cancers in the world, there is little known about the underlying regulatory mechanisms of miR-520 in colorectal cancer (CRC). In the present study, we investigated the expression of microRNA-520d-5p (miR-520d-5p) in CRC specimens and then explored its potential role and mechanism in CRC progression. We found that miR-520d-5p was markedly down-regulated in CRC clinical specimens compared with adjacent normal tissues by real-time PCR. Dual-luciferase assays confirmed that miR-520d-5p directly targeting CTHRC1 and SP1 transactivate miR-520d-5p by binding to its upstream promoter region. The biological functional experiments showed that ectopic re-expression of miR-520d-5p suppressed CRC cell proliferation, migration and invasion, whereas the inhibition of miR-520d-5p displayed an inverse effect in vitro and in vivo. Western blot shown that miR-520d-5p abrogated the epithelial-mesenchymal transition by inactivating the phosphorylation of Erk1/2. In conclusion, our findings indicate that miR-520d-5p is significantly down-expressed and involved in CRC progression and metastasis by targeting CTHRC1 and regulated by SP1, which provide new support for miR-520d-5p maybe as a novel anti-onco molecular target for the treatment of CRC in the future.

[Finite element analysis of lumbar fusion and Topping-off surgery].

OBJECTIVE: To evaluate the effect of Topping-off surgery on the adjacent segment of PLIF. METHODS: A finite element model of the human lumbar spine (L1-L5) was developed. The intact spinal model was validated by comparing it with previously reported models. Then, 2 models were analyzed and compared: (1) posterior lumbar interbody fusion (PLIF) at L4/5; (2) posterior lumbar interbody fusion at L4/5 and implantation of the interspinous spacer (ISP) at L3/4 (Topping-off). Then 500 N compressive loading plus 10 Nm moments simulating flexion, extension, lateral bending and axial rotation were imposed on both the L1 superior endplates. The ranges of motion, intradiscal pressures, facet stresses in L3/4, the stresses on spinous processes in L3 and L4 were investigated. All the measured data were analyzed by SPSS 21.0. RESULTS: The effect of the Topping-off on the adjacent segment appeared mainly in flexion-extension: the ranges of motion, intradiscal pressures (annulus and nucleus pulposus), both facet stresses were lower than that of the PLIF model, and the stresses on spinous processes in L3 and L4 were larger. Besides, the facet stresses on the left side in the left lateral bending were also lower than those of the PLIF model. CONCLUSION: Topping-off model is able to restrict the range of motion of the lumbar adjacent segment, decrease the intradiscal pressure and facet stresses, and has a potential effect of preventing adjacent segmental degeneration.