Multiple myeloma (MM) is one of the most common hematologic neoplastic diseases. Gossypol was once used as a male contraceptive but is considered a novel antitumor agent. This study aimed to reveal the gossypol-induced apoptosis mechanism and its hub genes. Gossypol-induced MM cell apoptosis is concentration- and time-dependent. Of a total of 532 differentially expressed genes, 273 genes were upregulated and 259 genes were downregulated in gossypol-treated MM cells. Through KEGG and WGCNA analyses, the apoptosis-associated module was identified, and JUN was identified as the hub gene. The expression of the JUN protein product c-Jun was downregulated in MM cell lines compared to that in normal plasma cells. High-risk MM patients had a lower expression of JUN. High-expression JUN group patients had a lower risk of death. JUN overexpression in MM cells induced potent cell death and growth inhibition by a caspase-dependent apoptotic mechanism. DR5 is one of the upstream receptors of the JNK pathway, and shRNA knockdown of DR5 can partially reverse gossypol-induced apoptosis. A total of 1017 genes were coexpressed with JUN in MM patients. These genes are mainly involved in other JNK-associated signaling pathways, such as the IL6, EGF and PDGF signaling pathways. In conclusion, JUN is identified as the hub gene in gossypol-induced apoptosis, and gossypol can activate caspase-dependent apoptosis through the JNK pathway by targeting c-Jun and other JNK-associated pathways. DR5 and IL6 are also involved in this mechanism.
Abstract Background The important role of the NFκBpathway in tumor development has long been recognized. but the role of the NFκB inhibitor family in liver cancer has not been studied. Hepatocellular carcinoma（HCC）has become a serious public health burden with high incidence, poor prognosis, and early detection, especially in Asia where hepatitis is prevalent. Methods The transcript level of the NFκB inhibitor family was investigated in HCC and normal tissues using Metabolic Gene Rapid Visualizer, UALCAN, and Tumor Immune Estimation Resource database（TIMER）respectively. Survival curves of NFKBIE were obtained using the Kaplan-Meier database. Genes co-expressed with NFKBIE in hepatocellular carcinoma were studied by LinkedOmics and Hepatocellular Carcinoma Database（HCCDB） respectively. Protein-protein interaction (PPI) Networks, gene ontology, and KEGG enrichment pathway analyses provide a novel method for investigating the NFKBIE mechanism in HCC. Using the TIMER database, the connection between immune infiltration and NFKBIE was determined. RNA-Seq was used to evaluate NFKBIE's function in HCC and its impact on proliferation and migration. Western Blot was used to confirm the expression of NFKBIE in HCC cell lines.In addition, we demonstrated NFKBIE overexpression in HCC using tissue microarrays encompassing 80 pairs of HCC and normal liver tissues. Results : NFKBIE was the only NFκBinhibitor in its family with high expression and a better prognosis in HCC.NFKBIE was correlated with clinical characteristics such as tumor grade, TP53 mutation status, and tumor stage.GSCA database suggested that NFKBIE might inhibit the PI3K/AKT, RAS/MAPK, RTK, and TSC/mTOR pathways. In addition, NFKBIE was significantly associated with B cell immune infiltration, and our RNA-Seq data showed that NFKBIE knockout significantly affected antigen presentation and hepatocellular carcinoma pathways. Immunohistochemistry on microarrays of tissue samples revealed that NFKBIE was overexpressed in various stages of HCC. Inhibition of NFKBIE also decreased the growth and migration of hepatocellular carcinoma cells. Conclusion ： Due to its prognostic value and overexpression in hepatocellular carcinoma, NFKBIE distinguished itself from other NFκB inhibitors. As such, it may provide a novel prognostic indicator and immunotherapeutic target in HCC.
Colon cancer, or colorectal cancer (CRC), is a type of cancer that develops from large bowel. Previous data has demonstrated that microRNAs (miRNAs) may be involved in the formation and progression of CRC. The deregulation of miR-708 has been identified in multiple types of cancer. However, to the best of our knowledge, there are no data concerning the expression and role of miR-708 in CRC.In this study, RT-PCR and Flow Cytometry were used to examine the expression and role of miR-708 and ZEB1 in proliferation and apoptosis. Transwell was used to examine the role of miR-708 and ZEB1 in invasion and migration. Western blot and qRT-PCR were conducted to determine the alteration of protein and miR-708 levels, respectively.MiR-708 was significantly downregulated in CRC tissues and cell lines. The restoration of the expression of miR-708 suppressed cell proliferation, induced apoptosis, and reduced metastasis in CRC in vitro. Additionally, bioinformatics analysis predicted ZEB1 as a novel target gene of miR-708. Furthermore, ZEB1 was upregulated in CRC, which was negatively correlated with miR-708 expression. Further studies showed that the overexpression of miR-708 and silence of ZEB1 inhibited stage of CRC via inhibiting AKT/mTOR signaling pathway in CRC cells.Taken together, these results indicate that miR-708 plays an important role in suppressing the development of CRC by directly targeting ZEB1 through AKT/mTOR signaling pathway, suggesting that miR-708 is a novel, effective therapeutic target for treating patients with CRC.
The important role of the nuclear factor κB (NFκB) pathway in tumour development has long been recognized; however, the role of the NFκB inhibitor family in liver cancer has not been elucidated. Hepatocellular carcinoma (HCC) is a serious public health burden with a high incidence, poor prognosis, and early detection, especially in Asia, where hepatitis is prevalent. In the present study, the mRNA expression level of the NFκB inhibitor family was assessed in HCC and normal tissues using the Metabolic Gene Rapid Visualizer, University of Alabama at Birmingham Cancer Data Analysis Portal, and the Tumor Immune Estimation Resource database (TIMER). Survival curves of nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor (NFKBI)E were obtained using the Kaplan-Meier method. Genes co-expressed with NFKBIE in HCC samples were studied using data from the LinkedOmics and the Hepatocellular Carcinoma Databases. Protein-protein interaction networks, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment pathway analyses were used to assess the NFKBIE mechanism in HCC. Using the TIMER database, the association between immune infiltration and NFKBIE was determined. RNA-sequencing (RNA-seq) was used to evaluate the function of NFKBIE in HCC and its impact on proliferation and migration. Western blotting was used to confirm the expression of NFKBIE in HCC cell lines. In addition, NFKBIE overexpression in HCC was demonstrated using tissue microarrays encompassing 80 pairs of HCC and normal liver tissues. NFKBIE was the only NFκB inhibitor with high expression and an improved prognosis in HCC compared with other NFκB inhibitors. NFKBIE was correlated with clinical characteristics, such as tumour grade, tumour protein P53 mutation status and tumour stage. Data obtained from Gene Set Cancer Analysis suggested that NFKBIE may inhibit the PI3K/AKT, RAS/MAPK, RTK and TSC/mTOR pathways. In addition, NFKBIE was significantly associated with B-cell immune infiltration and the RNA-seq data demonstrated that knockdown of NFKBIE significantly affected 'Antigen processing and presentation' and 'hepatocellular carcinoma' pathways. Immunohistochemistry of microarrays of tissue samples revealed that NFKBIE was overexpressed in several stages of HCC. Finally, inhibition of NFKBIE decreased the proliferation and migration of HCC cells. In conclusion, due to its prognostic value and overexpression in HCC, NFKBIE distinguished itself from other NFκB inhibitors. As such, it may provide a novel prognostic indicator and immunotherapeutic target for HCC.
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