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Background Chromobox protein homolog 7 (CBX7), a member of the polycomb group (PcG) family of proteins, is involved in the regulation of cell proliferation and cancer progression. PcG family members, such as BMI, Mel-18, and EZH2, are integral constituents of the polycomb repressive complexes (PRCs) and have been known to regulate cancer stem cell (CSC) phenotype. However, the role of other PRCs’ constituents such as CBX7 in the regulation of CSC phenotype remains largely elusive. This study was to investigate the role of CBX7 in regulating stem cell-like properties of gastric cancer and the underlying mechanisms. Methods Firstly, the role of CBX7 in regulating stem cell-like properties of gastric cancer was investigated using sphere formation, Western blot, and xenograft tumor assays. Next, RNA interference and ectopic CBX7 expression were employed to determine the impact of CBX7 on the expression of CSC marker proteins and CSC characteristics. The expression of CBX7, its downstream targets, and stem cell markers were analyzed in gastric stem cell spheres, common cancer cells, and gastric cancer tissues. Finally, the pathways by which CBX7 regulates stem cell-like properties of gastric cancer were explored. Results We found that CBX7, a constituent of the polycomb repressive complex 1 (PRC1), plays an important role in maintaining stem cell-like characteristics of gastric cancer cells via the activation of AKT pathway and the downregulation of p16. Spearman rank correlation analysis showed positive correlations among the expression of CBX7 and phospho-AKT (pAKT), stem cell markers OCT-4, and CD133 in gastric cancer tissues. In addition, CBX7 was found to upregulate microRNA-21 (miR-21) via the activation of AKT-NF-κB pathway, and miR-21 contributes to CBX7-mediated CSC characteristics. Conclusions CBX7 positively regulates stem cell-like characteristics of gastric cancer cells by inhibiting p16 and activating AKT-NF-κB-miR-21 pathway.

[This corrects the article DOI: 10.3389/fcell.2022.993525.].

Cancer is a complex and multifaceted disease characterized by uncontrolled cell growth, genetic alterations, and disruption of normal cellular processes, leading to the formation of malignant tumors with potentially devastating consequences for patients. Molecular research is important in the diagnosis and treatment, one of the molecular mechanisms involved in various cancers is the fluctuation of gene expression. Non-coding RNAs, especially microRNAs, are involved in different stages of cancer. MicroRNAs are small RNA molecules that are naturally produced within cells and bind to the 3ʹ-UTR of target mRNA, repressing gene expression by regulating translation. Overexpression of miR-19a has been reported in human malignancies. Upregulation of miR-19a as a member of the miR-17–92 cluster is key to tumor formation, cell proliferation, survival, invasion, metastasis, and drug resistance. Furthermore. bioinformatics and in vitro data reveal that the miR-19a-3p isoform binds to the 3ʹUTR of CBX7 and was identified as the miR-19a-3p target gene. CBX7 is known as a tumor suppressor. This review initially describes the regulation of mir-19a in multiple cancers. Accordingly, the roles of miR-19 in affecting its target gene expression CBX7 in carcinoma also be discussed. Graphical abstract

Multiple studies have shown knockdown of chromobox 7 (CBX7) promotes the regenerative capacity of various cells or tissues. We examined the effect of CBX7 on hepatocyte proliferation and liver regeneration after 2/3 hepatectomy in a mouse model. For in vitro experiments, NCTC 1469 and BNL CL.2 hepatocytes were co-transfected with siRNA-CBX7-1 (si-CBX7-1), siRNA-CBX7-2 (si-CBX7-2), pcDNA-CBX7, si-BMI1-1, si-BMI1-2, pcDNA-BMI1, or their negative control. For in vivo experiments, mice were injected intraperitoneally with lentivirus-packaged shRNA and shRNA CBX7 before hepatectomy. Our results showed that CBX7 was rapidly induced in the early stage of liver regeneration. CBX7 regulated hepatocyte proliferation, cell cycle, and apoptosis of NCTC 1469 and BNL CL.2 hepatocytes. CBX7 interacted with BMI1 and inhibited BMI1 expression in hepatocytes. Silencing BMI1 aggregated the inhibitory effect of CBX7 overexpression on hepatocyte viability and the promotion of apoptosis. Furthermore, silencing BMI1 enhanced the regulatory effect of CBX7 on Nrf2/ARE signaling in HGF-induced hepatocytes. In vivo, CBX7 silencing enhanced liver/body weight ratio in PH mice. CBX7 silencing promoted the Ki67-positive cell count and decreased the Tunel-positive cell count after hepatectomy, and also increased the expression of nuclear Nrf2, HO-1, and NQO-1. Our results suggest that CBX7 silencing may increase survival following hepatectomy by promoting liver regeneration.

Striking similarity exists between metabolic changes associated with embryogenesis and tumorigenesis. Chromobox proteins‐CBX2/4/6/7/8, core components of canonical polycomb repressor complex 1, play essential roles in embryonic development and aberrantly expressed in breast cancer. Understanding how altered CBX expression relates to metabolic reprogramming in breast cancer may reveal vulnerabilities of therapeutic pertinence. Using transcriptomic and metabolomic data from breast cancer patients (N > 3000 combined), we performed pathway‐based analysis and identified outstanding roles of CBX2 and CBX7 in positive and negative regulation of glucose metabolism, respectively. Genetic ablation experiments validated the contrasting roles of two isoforms in cancer metabolism and cell growth. Furthermore, we provide evidence for the role of mammalian target of rapamycin complex 1 signaling in mediating contrary effects of CBX2 and CBX7 on breast cancer metabolism. Underpinning the biological significance of metabolic roles, CBX2 and CBX7 were found to be the most up‐ and downregulated isoforms, respectively, in breast tumors compared with normal tissues. Moreover, CBX2 and CBX7 expression (not other isoforms) correlated strongly, but oppositely, with breast tumor subtype aggressiveness and the proliferation markers. Consistently, genomic data also showed higher amplification frequency of CBX2, not CBX7, in breast tumors. Highlighting the clinical significance of findings, disease‐specific survival and drug sensitivity analysis revealed that CBX2 and CBX7 predicted patient outcome and sensitivity to FDA‐approved/investigational drugs. In summary, this work identifies novel cross talk between CBX2/7 and breast tumor metabolism, and the results presented may have implications in strategies targeting breast cancer. This study shows that chromobox protein (CBX)2 and CBX7 are differentially expressed in normal and breast tumor, and have opposite effects on glycolysis. In normal cells, lower CBX2 and higher CBX7 expression inhibits abnormal cell proliferation. By contrast, increased CBX2 and decreased CBX7 in tumor cells result in augmented glycolysis, which in turn supports tumor cell proliferation.

Clear cell renal cell carcinoma (ccRCC) accounts for 85% of all malignant renal tumors. Currently, the pathogenesis of ccRCC is not fully understood. Chromobox (CBX) family proteins are the major subunits of PcG complexes and are implicated in regulating mammalian development. The CBX family consists of eight members, namely, CBX1-8. Numerous studies have highlighted that each CBX protein exhibits distinct functions and prognostic roles in specific cancer types. In this study, in silico analysis indicated that CBX7 was downregulated in ccRCC and correlated with favorable prognosis in a ccRCC cohort. Subsequent studies showed that CBX7 inhibited cancer cell proliferation and invasion. Then, we showed that CBX7 downregulated ETS1 to inactivate the tumor necrosis factor (TNF) signaling pathway, which inhibited tumor proliferation and enhanced the sensitivity of ccRCC cells to tyrosine kinase inhibitors (TKIs). Moreover, we found that CBX7 was a bona fide substrate of RNF26. RNF26 promoted the degradation of CBX7 and enhanced ccRCC tumor growth. Therefore, our results revealed a novel RNF26/CBX7 axis that modulates the TNF signaling pathway in ccRCC.

To investigate the association between the lncRNA NEAT1 and breast cancer, and to determine the influence of NEAT1 on regulation of other signaling molecules in breast cancer. In the present study, we measured levels of the lncRNA NEAT1 in 106 breast cancer patients and in a human breast cancer cell line by qRT-PCR. The correlation between NEAT1 expression and patients' clinical characteristics was analyzed with in-house and TCGA data. We used cellular functioning assays and cell immunofluorescence assay to evaluate the role of NEAT1 and its target molecules in proliferation, invasion and migration in breast cancer. We used Western blotting to explore possible targets of NEAT1 and a subcellular fractionation assay to locate NEAT1 expression. NEAT1 was overexpressed in breast cancer tissue and also closely related to advanced clinical stages and positive lymph node metastases. NEAT1 levels were also tightly correlated to prognosis for breast cancer patients in survival analyses. Cellular function assays revealed that downregulation of NEAT1 could inhibit breast cancer cell viability, invasion and migration. Western blotting revealed down-regulation of CBX7 and up-regulation of RTCB following NEAT1 inhibition. Based on the cytoplasmic and nuclear expression of NEAT1, we investigated the possible regulation of CBX7 and RTCB by NEAT1. Results showed that NEAT1 regulated the expression of CBX7 and RTCB, possibly by binding of NEAT1 to DNA in the nucleus, which facilitates cell proliferation, invasion and migration. The current results suggest that the lncRNA NEAT1 is upregulated in breast cancer and facilitates tumor cell viability, invasion and migration via CBX7 and RTCB.

Cervical cancer stands as the most frequently diagnosed malignancy affecting the female reproductive. The erythropoietin-producing hepatocyte (Eph) family tyrosine kinases play important roles in tumorigenesis and cancer aggression. However, the exact role of EPHB6 in cervical cancer remains unknown. The present study investigated the role of EPHB6 in the malignant process of cervical cancer. GEPIA, tnmplot and kmplot database was used to study the expression of EPHB6 in cervical cancer tissues. western blotting was used to detect the expression of EPHB6, CyclinD, CDK4, CDK6, CBX7, MMP2 and MMP9. CCK8 and EDU staining were used to detect cell proliferation. Wound healing and transwell were used to detect cell proliferation and migration. Flow cytometry was used to detect cell cycle level. The linkedomics database was used to predict the correlation of EPHB6 and CBX7 in cervical cancer. Subsequently, HDOCK server was used to predict the combination of EPHB6 and CBX7. Our current results suggested that the expression of EPHB6 is reduced in cervical cancer tissues and cell lines, and the lower the expression, the worse the prognosis. Moreover, overexpression of EPHB6 inhibits cell proliferation, invasion and migration and cycle acceleration of C33A cells. Furthermore, EPHB6 and CBX7 bind to each other in C33A cells, and EPHB6 inhibits cell proliferation, invasion, migration and cell cycle acceleration in cervical cancer by binding to CBX7. EPHB6 expression is reduced in cervical cancer tissues and cells. Its overexpression inhibits proliferation, invasion, migration, and cell cycle acceleration in C33A cells, exhibiting synergy when bound to CBX7.

Background Chemotherapy incorporating the proteasome inhibitor bortezomib (BTZ) has improved outcomes for patients with multiple myeloma (MM); however, resistance to chemotherapy and disease relapse remain significant challenges, closely associated with cellular senescence. This study investigated the key drivers of myeloma cell senescence and its role in MM progression. Methods Flow cytometry assessed senescence-associated β-galactosidase (SA-β-gal) activity in myeloma cells from bone marrow samples of MM patients. BTZ was used to establish cell senescence model. RNA-seq identified key genes regulating myeloma cell senescence, which were verified by qPCR. After CBX7 knockdown and overexpression, SA-β-gal staining, CCK-8 assay, cell cycle assay, and colony formation assay were performed to investigate its effects on senescence. RNA-seq further identified downstream target genes and pathways, and small interfering RNA and ERK inhibitor were used to explore their effects. A xenograft mouse model was used to validate CBX7’s effect on myeloma cell senescence. Results Our results demonstrated that BTZ-based chemotherapy induces senescence in myeloma cells, with SA-β-gal activity linked to malignant proliferation. CBX7 was identified as a critical regulator of cellular senescence in myeloma cells. Elevated CBX7 levels were observed in newly diagnosed MM, decreased during remission, and increased again at relapse. CBX7 levels positively correlated with blast counts, creatinine, and β2-microglobulin levels, and negatively correlated with SA-β-gal activity. Functionally, CBX7 knockdown promoted BTZ-induced myeloma cell senescence and senescence-like growth arrest, whereas CBX7 overexpression had the opposite effect. Mechanistically, CBX7 regulates senescence-like growth arrest in myeloma cells via the ERK/STAT3/MIX1 axis. Silencing PIM1 or the ERK inhibitor U0126 mitigated CBX7-mediated myeloma cell senescence and enhanced the inhibitory effects of BTZ on cell viability and clone formation. In vivo, CBX7 knockdown enhanced BTZ-inhibited xenograft tumor growth. Conclusion CBX7 is a pivotal target for regulating cellular senescence in myeloma cells, operating through a novel CBX7/ERK/PIM1 regulatory axis. Targeting CBX7 and its downstream pathways may augment the efficacy of standard chemotherapy.