HOXA6-HOXA5遺伝子座の新規長鎖ノンコーディングRNAは大腸癌細胞の増殖を促進する

Background : Homeobox A5 (HOXA5), a member of the HOX family, plays an important role in tumor development and morphogenesis, although opposite effects on tumorigenesis have been observed, depending on the tissue type. In this study, we aimed to investigate the role of a novel transcript from the HOXA6-HOXA5 locus in colon cancer tumorigenesis. Methods : Human colon cancer cell lines were analyzed using next generation sequencing-based targeted mRNA capture. The effects of overexpression and silencing of HOXA5 transcripts were evaluated in vitro and using a xenograft nude mouse model. Results : We identified three novel transcripts (HOXA5 short, long 1, and long 2) transcribed from the HOXA6-HOXA5 locus in HCT116 colon cancer cells using next generation sequencing-based targeted mRNA capture. Knockdown of HOXA5 long 1 and long 2 transcripts did not affect cell growth, while selective silencing of HOXA5 short RNA inhibited cell growth independent of HOXA5 expression. Stable overexpression of HOXA5 short RNA promoted proliferation and migration of colon cancer cell lines HCT116, DLD1, and HT-29 and accelerated tumor growth in the xenograft mouse model. In vitro translation assays suggested HOXA5 short RNA was a functional long non-coding RNA (lncRNA). Consistent with these observations, expression of HOXA5 short RNA was upregulated in advanced colon cancer tissues. Ingenuity Pathway Analysis of differentially expressed genes between HOXA5 short RNA overexpressed and silenced HCT116 cells revealed that HOXA5 short RNA preferentially modified expression of epidermal growth factor (EGF) signal-related genes. Western blot analysis demonstrated that stable overexpression of HOXA5 short RNA increased EGF receptor levels and facilitated its phosphorylation in both HCT116 cells and xenograft tumors. Conclusions : Our results suggested that HOXA5 short RNA, a novel lncRNA, may play a crucial role in colon tumor growth through activation of EGF signaling

社会経済的格差のネガティブな認識と抑うつ気分は末梢血白血球のPPBPとSLC1A7 遺伝子の発現を低下させる

Inequality in socioeconomic status (SES) is associated with an increased risk for the development of mental health problems. Here, we examined the association between socioeconomic status (SSS) and psychological distress, and measured gene expression signatures in peripheral blood leukocytes responsible for this association, in 129 healthy adults (27 males and 102 females, aged 44.0 ± 13.0 years) working in a private hospital in Japan. Depressive mood was assessed by Zung Selfrating Depression Scale (SDS). A multiple regression analysis adjusted for gender and age showed that subjective SSS was independently and negatively associated with SDS score. We next focused on 9 subjects who exhibited low SSS scores and 11 subjects with high SSS scores. Microarray analysis revealed that levels of 522 mRNAs were differentially expressed in periheral leukocytes between low and high-SSS groups. The differentially expressed genes were preferentially involved in cellular movement or inflammatory responses. Among them, mRNA levels of pro-platelet basic protein (PPBP) and solute carrier family 1 (glutamine transporter), member 7 (SLC1A7) were negatively correlated with SSS scores. Our results re-confirmed the association between negative perception of SES and depressive mood in healthy adults, and suggest a possible involvement of PPBP and SLC1A7 in the association

Serine/arginine-rich splicing factor 7 regulates p21-dependent growth arrest in colon cancer cells

Serine/arginine-rich splicing factors (SRSFs) play wide-ranging roles in gene expression through post-transcriptional regulation as well as pre-mRNA splicing. SRSF7 was highly expressed in colon cancer tissues, and its knockdown inhibited cell growth in colon cancer cells (HCT116) in association with altered expression of 4,499 genes. The Ingenuity Pathway Analysis revealed that cell cycle-related canonical pathways were ranked as the highly enriched category in the affected genes. Western blotting confirmed that p21, a master regulator in cell cycle, was increased without any induction of p53 in SRSF7 knockdown cells. Furthermore, cyclin-dependent kinase 2 and retinoblastoma protein were remained in the hypophosphorylated state. In addition, the SRSF7 knockdown-induced cell growth inhibition was observed in p53-null HCT116 cells, suggesting that p53-independent pathways were involved in the SRSF7 knockdown-induced cell growth inhibition. The reduction of SRSF7 stabilized cyclin-dependent kinase inhibitor 1A (CDKN1A) mRNA without any activation of the CDKN1A promoter. Interestingly, SRSF7 knockdown also blocked p21 degradation. These results suggest that the reduction of SRSF7 post-transcriptionally regulates p21 induction at the multistep processes. Thus, the present findings disclose a novel, important role of SRSF7 in cell proliferation through regulating p21 levels

ヌクレオリンは、超保存領域を含むTRA2β4を核内に保持し、大腸がん細胞の増殖を促進する

Transcribed-ultraconserved regions (T-UCRs), which contain conserved sequences with 100% identity across human, rat and mouse species, are a novel category of functional RNAs. The human transformer 2β gene (TRA2B) encodes a UCR that spans exon 2 (276 bp) and its neighboring introns. Among five spliced RNA variants (TRA2β1-5) transcribed from the TRA2B gene, only TRA2β4 contains the conserved exon 2. TRA2β4 is overexpressed in colon cancer cells and accelerates cell growth by blocking the transcription of CDKN1A. However, the mechanisms underlying the overexpression of TRA2β4 in colon cancer cells are unknown. Using biotinylated RNA pull-down assays followed by liquid chromatography-mass spectrometric analysis, we identified nucleolin as a TRA2β4-binding protein. Knockdown of nucleolin reduced the nuclear retention of TRA2β4 and accelerated its degradation in the cytoplasm, whereas nucleolin overexpression increased TRA2β4 levels and its mitogenic activity. Nucleolin directly bound to TRA2β4 exon 2 via the glycine/arginine-rich (GAR) domain. Overexpression of GAR-deficient nucleolin failed to increase TRA2β4 expression and growth of colon cancer cells. RNA fluorescence in situ hybridization showed that TRA2β4 co-localized with nucleolin in nuclei but not with the mutant lacking GAR. Our results suggest that specific interactions between nucleolin and UCR-containing TRA2β4 may be associated with abnormal growth of colon cancer cells

先天性血友病患者の移行期の実態

【Introduction】Congenital hemophilia is a category of hemorrhagic disease caused by a genetic defect in the production of coagulation factors. It is treated by administering regular coagulation factor injections on an ongoing basis. Hemophilia is a hereditary illness, often causing social and psychological problems as a result of the disease. To analyze the objective effects of hemophilia, we conducted a retrospective analysis in Tokushima University Hospital. 【Result】All ２３ cases were men between the ages of２０and７２. Hemophilia A was present in１７cases, and hemophilia B was present in six. Nineteen out of ２３ cases were severe, and the others were intermediate. Medical assessments were conducted at pediatrics in seven cases and hematology in １６ cases. Adoption of the self-injection technique was not realized in five cases. Seventeen cases were complicated by hemophilic arthropathy, seven with human immunodeficiency virus（HIV）, and １２ with hepatitis C virus. Eight participants were unemployed, and１７were unmarried. 【Discussion】 Many adult hemophilia patients still visit pediatrics in our hospital. Hemophilia in the period of growth between adolescence and young adulthood is often accompanied by life-altering events such as entering higher education, marriage, and work experience. Therefore, collaboration among professionals of multiple occupations, such as doctors, nurses, pharmacists, medical social workers, and clinical psychologists, is essential. Furthermore, there are many cases of HIV and hepatitis C virus infections complicating hemophilia study due to the stigma surrounding HIV-tainted blood. 【Conclusion】It is imperative that we establish a long-term, sustainable, and multi-disciplinary transitional care and medical support system for patients and their families

Physical and functional interaction between DDB and XPA in nucleotide excision repair

Damaged DNA-binding protein (DDB), consisting of DDB1 and DDB2 subunits recognizes a wide spectrum of DNA lesions. DDB is dispensable for in vitro nucleotide excision repair (NER) reaction, but stimulates this reaction especially for cyclobutane pyrimidine dimer (CPD). Here we show that DDB directly interacts with XPA, one of core NER factors, mainly through DDB2 subunit and the amino-acid residues between 185 and 226 in XPA are important for the interaction. Interestingly, the point mutation causing the substitution from Arg-207 to Gly, which was previously identified in a XP-A revertant cell-line XP129, diminished the interaction with DDB in vitro and in vivo. In a defined system containing R207G mutant XPA and other core NER factors, DDB failed to stimulate the excision of CPD, although the mutant XPA was competent for the basal NER reaction. Moreover, in vivo experiments revealed that the mutant XPA is recruited to damaged DNA sites with much less efficiency compared with wild-type XPA and fails to support the enhancement of CPD repair by ectopic expression of DDB2 in SV40-transformed human cells. These results suggest that the physical interaction between DDB and XPA plays an important role in the DDB-mediated NER reaction

A novel long non-coding RNA from the HOXA6-HOXA5 locus facilitates colon cancer cell growth

Background : Homeobox A5 (HOXA5), a member of the HOX family, plays an important role in tumor development and morphogenesis, although opposite effects on tumorigenesis have been observed, depending on the tissue type. In this study, we aimed to investigate the role of a novel transcript from the HOXA6-HOXA5 locus in colon cancer tumorigenesis. Methods : Human colon cancer cell lines were analyzed using next generation sequencing-based targeted mRNA capture. The effects of overexpression and silencing of HOXA5 transcripts were evaluated in vitro and using a xenograft nude mouse model. Results : We identified three novel transcripts (HOXA5 short, long 1, and long 2) transcribed from the HOXA6-HOXA5 locus in HCT116 colon cancer cells using next generation sequencing-based targeted mRNA capture. Knockdown of HOXA5 long 1 and long 2 transcripts did not affect cell growth, while selective silencing of HOXA5 short RNA inhibited cell growth independent of HOXA5 expression. Stable overexpression of HOXA5 short RNA promoted proliferation and migration of colon cancer cell lines HCT116, DLD1, and HT-29 and accelerated tumor growth in the xenograft mouse model. In vitro translation assays suggested HOXA5 short RNA was a functional long non-coding RNA (lncRNA). Consistent with these observations, expression of HOXA5 short RNA was upregulated in advanced colon cancer tissues. Ingenuity Pathway Analysis of differentially expressed genes between HOXA5 short RNA overexpressed and silenced HCT116 cells revealed that HOXA5 short RNA preferentially modified expression of epidermal growth factor (EGF) signal-related genes. Western blot analysis demonstrated that stable overexpression of HOXA5 short RNA increased EGF receptor levels and facilitated its phosphorylation in both HCT116 cells and xenograft tumors. Conclusions : Our results suggested that HOXA5 short RNA, a novel lncRNA, may play a crucial role in colon tumor growth through activation of EGF signaling

Negative perception of socioeconomic status with depressive mood down-regulates expression of <i>PPBP</i> and <i>SLC1A7</i> genes in peripheral blood leukocytes

<p>Inequality in socioeconomic status (SES) is associated with an increased risk for the development of mental health problems. Here, we examined the association between socioeconomic status (SSS) and psychological distress, and measured gene expression signatures in peripheral blood leukocytes responsible for this association, in 129 healthy adults (27 males and 102 females, aged 44.0 ± 13.0 years) working in a private hospital in Japan. Depressive mood was assessed by Zung Self-rating Depression Scale (SDS). A multiple regression analysis adjusted for gender and age showed that subjective SSS was independently and negatively associated with SDS score. We next focused on 9 subjects who exhibited low SSS scores and 11 subjects with high SSS scores. Microarray analysis revealed that levels of 522 mRNAs were differentially expressed in periheral leukocytes between low and high-SSS groups. The differentially expressed genes were preferentially involved in cellular movement or inflammatory responses. Among them, mRNA levels of <i>pro</i>-<i>platelet basic protein</i> (<i>PPBP</i>) and <i>solute carrier family 1</i> (<i>glutamine transporter</i>), <i>member 7</i> (<i>SLC1A7</i>) were negatively correlated with SSS scores. Our results re-confirmed the association between negative perception of SES and depressive mood in healthy adults, and suggest a possible involvement of <i>PPBP</i> and <i>SLC1A7</i> in the association.</p

"湿式化学分析とXAFS法によるFe, Ce共存ガラス中のCeの平均価数評価法開発"

identifier:oai:t2r2.star.titech.ac.jp:5067676