ABSTRACT
We investigated the mechanisms of action of immuno-modulatory drug (lenalidomide) on the protein expression of cereblon (CRBN) and their therapeutic targets in the multiple myeloma cell line RPMI8226. The multiple myeloma cell line RPMI8226 was cultured and treated with different concentrations of lenalidomide and bortezomib to determine the proliferation inhibition rate, apoptosis rate, and protein expression of CRBN. The results revealed that both lenalidomide and bortezomib inhibited the proliferation of RPMI8226 and promoted cell apoptosis. However, the protein expression of CRBN decreased signifi-cantly after treatment with lenalidomide, while bortezomib had no effect on the expression of CRBN. We confirmed that CRBN may be a target of lenalidomide.
Subject(s)
Multiple Myeloma/metabolism , Peptide Hydrolases/metabolism , Thalidomide/analogs & derivatives , Adaptor Proteins, Signal Transducing , Apoptosis/drug effects , Blotting, Western , Bortezomib/pharmacology , Cell Line, Tumor , Humans , Lenalidomide , Thalidomide/pharmacology , Ubiquitin-Protein LigasesABSTRACT
Genetic factors have been shown to be associated with the risk of stroke. However, due to individual differences, the extent of the association between genetic factors and stroke varies widely. Hypertension is considered one of the most important risk factors for stroke, but it remains unknown whether the genetic association with stroke in a hypertensive population is the same as that in a non-hypertensive population. The aim of the present study was to explore the association between the phosphodiesterase 4D gene (PDE4D) and interleukin-6 receptor gene (IL6R) single nucleotide polymorphisms and ischemic stroke in a hypertensive population. The study included 307 ischemic stroke cases with hypertension and 227 controls (simple hypertension). The polymorphic loci rs12188950 and rs918592 in PDE4D, and rs4075015 and rs4537545 in IL6R were selected for analyzing the genotype and allele frequencies between cases and controls. rs12188950 was not found in the study population. In the univariate analysis, the rs918592 polymorphism in PDE4D was found to be significantly associated with ischemic stroke with the recessive model (P = 0.02), whereas no association with ischemic stroke was observed for rs4075015 and rs4537545 in IL6R. Following adjustment for binary logistic regression, the rs918592 polymorphism was not found to be associated with ischemic stroke. While prior studies have found an association between PDE4D and IL6R polymorphisms and ischemic stroke, our results suggest that this association may be different in a hypertensive population. Therefore, the association between PDE4D and IL6R polymorphisms and ischemic stroke among a hypertensive population requires further investigation.
Subject(s)
Brain Ischemia/genetics , Cyclic Nucleotide Phosphodiesterases, Type 4/genetics , Hypertension/genetics , Interleukin-6/genetics , Polymorphism, Single Nucleotide , Stroke/genetics , Alleles , Asian People , Brain Ischemia/complications , Brain Ischemia/diagnosis , Brain Ischemia/ethnology , Case-Control Studies , Disease Susceptibility , Gene Expression , Gene Frequency , Genetic Association Studies , Haplotypes , Humans , Hypertension/complications , Hypertension/diagnosis , Hypertension/ethnology , Linkage Disequilibrium , Logistic Models , Odds Ratio , Risk Factors , Stroke/complications , Stroke/diagnosis , Stroke/ethnologyABSTRACT
Overexpression of cytokine-induced apoptosis inhibitor 1 (CIAPIN1) contributes to multidrug resistance (MDR) in breast cancer. This study aimed to evaluate the potential of CIAPIN1 gene silencing by RNA interference (RNAi) as a treatment for drug-resistant breast cancer and to investigate the effect of CIAPIN1 on the drug resistance of breast cancer in vivo. We used lentivirus-vector-based RNAi to knock down CIAPIN1 in nude mice bearing MDR breast cancer tumors and found that lentivirus-vector-mediated silencing of CIAPIN1 could efficiently and significantly inhibit tumor growth when combined with chemotherapy in vivo. Furthermore, Western blot analysis showed that both CIAPIN1 and P-glycoprotein expression were efficiently downregulated, and P53 was upregulated, after RNAi. Therefore, we concluded that lentivirus-vector-mediated RNAi targeting of CIAPIN1 is a potential approach to reverse MDR of breast cancer. In addition, CIAPIN1 may participate in MDR of breast cancer by regulating P-glycoprotein and P53 expression.
Subject(s)
Animals , Female , Humans , Antibiotics, Antineoplastic/therapeutic use , Breast Neoplasms/drug therapy , Doxorubicin/therapeutic use , Drug Resistance, Neoplasm/genetics , Gene Silencing , Intracellular Signaling Peptides and Proteins/genetics , Blotting, Western , Breast Neoplasms/genetics , Carcinoma/drug therapy , Carcinoma/genetics , Disease Models, Animal , Genes, MDR , Genetic Vectors/genetics , Growth Inhibitors/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Lentivirus/genetics , Mice, Inbred BALB C , Mice, Nude , ATP Binding Cassette Transporter, Subfamily B, Member 1/drug effects , RNA Interference , RNA, Small Interfering/genetics , /drug effectsABSTRACT
Overexpression of cytokine-induced apoptosis inhibitor 1 (CIAPIN1) contributes to multidrug resistance (MDR) in breast cancer. This study aimed to evaluate the potential of CIAPIN1 gene silencing by RNA interference (RNAi) as a treatment for drug-resistant breast cancer and to investigate the effect of CIAPIN1 on the drug resistance of breast cancer in vivo. We used lentivirus-vector-based RNAi to knock down CIAPIN1 in nude mice bearing MDR breast cancer tumors and found that lentivirus-vector-mediated silencing of CIAPIN1 could efficiently and significantly inhibit tumor growth when combined with chemotherapy in vivo. Furthermore, Western blot analysis showed that both CIAPIN1 and P-glycoprotein expression were efficiently downregulated, and P53 was upregulated, after RNAi. Therefore, we concluded that lentivirus-vector-mediated RNAi targeting of CIAPIN1 is a potential approach to reverse MDR of breast cancer. In addition, CIAPIN1 may participate in MDR of breast cancer by regulating P-glycoprotein and P53 expression.
Subject(s)
Antibiotics, Antineoplastic/therapeutic use , Breast Neoplasms/drug therapy , Doxorubicin/therapeutic use , Drug Resistance, Neoplasm/genetics , Gene Silencing , Intracellular Signaling Peptides and Proteins/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/drug effects , Animals , Blotting, Western , Breast Neoplasms/genetics , Carcinoma/drug therapy , Carcinoma/genetics , Disease Models, Animal , Female , Genes, MDR , Genetic Vectors/genetics , Growth Inhibitors/genetics , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Lentivirus/genetics , MCF-7 Cells , Mice, Inbred BALB C , Mice, Nude , RNA Interference , RNA, Small Interfering/genetics , Tumor Suppressor Protein p53/drug effectsABSTRACT
Mutations in the myostatin (MSTN) gene can inactivate its expression and result in a non-functional protein, which leads to dramatic muscularity and a "double-muscling" phenomenon in many species. Using gene sequencing and polymerase chain reaction-single-strand conformation polymorphism methods, polymorphisms of the MSTN gene were investigated as a candidate marker for growth in 288 goats. The results showed 2 novel single nucleotide polymorphisms: DQ167575 g.197G>A and 345A>T. Three potential genotypes (AA, AB, and BB) of substitution 197G>A in the 5'-untranslated region were detected in the 2 breeds. The polymorphism (CC and CD) of substitution 345A>T in exon I was segregated. The genetic diversity analysis revealed that Boer goat and Anhui white goat possessed intermediate genetic diversity in the P1 and P3 loci. Significant associations between the genotypes of the P3 locus and body weight, body length, and body height were observed in Boer goat and Anhui white goat (P < 0.05). It could be inferred that the MSTN gene may be a major gene or linked to the major gene affecting the goat growth traits. The polymorphic site could be a molecular marker-assisted selection program for body weight.