掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Long noncoding RNAs (lncRNAs) play pivotal roles in tumor development. To identify dysregulated lncRNAs in gastric cancer (GC), we analyzed genome-wide trimethylation of histone H3 lysine 4 (H3K4me3) to screen for transcriptionally active lncRNA genes in the non-tumorous gastric mucosa of patients with GC and healthy individuals. We found that H3K4me3 at TM4SF1-AS1 was specifically upregulated in GC patients and that the expression of TM4SF1-AS1 was significantly elevated in primary and cultured GC cells. TM4SF1-AS1 contributes to GC cell growth in vitro and in vivo, and its oncogenic function is mediated, at least in part, through interactions with purine-rich element-binding protein α (Pur-α) and Y-box binding protein 1 (YB-1). TM4SF1-AS1 also activates interferon signaling in GC cells, which is dependent on Pur-α and RIG-I. Chromatin isolation by RNA purification (ChIRP)-mass spectrometry demonstrated that TM4SF1-AS1 was associated with several stress granule (SG)-related proteins, including G3BP2, RACK1, and DDX3. Notably, TM4SF1-AS1 promoted SG formation and inhibited apoptosis in GC cells by sequestering RACK1, an activator of the stress-responsive MAPK pathway, within SGs. TM4SF1-AS1-induced SG formation and apoptosis inhibition are dependent on Pur-α and YB-1. These findings suggested that TM4SF1-AS1 contributes to tumorigenesis by enhancing SG-mediated stress adaptation.

その他リンク： https://www.nature.com/articles/s41419-023-05953-3

DOI： 10.1038/s41419-023-05953-3

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: While molecular targeted drugs and other therapies are being developed for many tumors, pancreatic cancer is still considered to be the malignant tumor with the worst prognosis. We started this study to identify prognostic genes and therapeutic targets of pancreatic cancer. METHODS: To comprehensively identify prognostic genes in pancreatic cancer, we investigated the correlation between gene expression and cancer-specific prognosis using transcriptome and clinical information datasets from The Cancer Genome Atlas (TCGA). In addition, we examined the effects of the suppression of candidate prognostic genes in pancreatic cancer cell lines. RESULT: We found that patients with high expression levels of MYEOV, a primate-specific gene with unknown function, had significantly shorter disease-specific survival times than those with low expression levels. Cox proportional hazards analysis revealed that high expression of MYEOV was significantly associated with poor survival and was an independent prognostic factor for disease-specific survival in pancreatic cancer patients. Analysis of multiple cancer samples revealed that the MYEOV promoter region is methylated in noncancer tissues but is demethylated in tumors, causing MYEOV overexpression in tumors. Notably, the knockdown of MYEOV suppressed the expression of MTHFD2 and other folate metabolism-related enzyme genes required for the synthesis of amino acids and nucleic acids and also restored the expression of c-Myc and mTORC1 repressors. CONCLUSION: There is a significant correlation between elevated MYEOV expression and poor disease-specific survival in pancreatic cancer patients. MYEOV enhances the activation of several oncogenic pathways, resulting in the induction of pancreatic cancer cell proliferation. Overall, MYEOV acts as an oncogene in pancreatic cancer. Furthermore, MYEOV may be a prognostic biomarker and serve as an 'actionable' therapeutic target for pancreatic cancers.

DOI： 10.1186/s12885-022-10433-6

PubMed

researchmap

掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/genes13061085

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Tropomyosin receptor kinase (TRK) inhibitors have demonstrated histology-agnostic efficacy in patients with neurotrophic receptor tyrosine kinase (NTRK) gene fusion. Although responses to TRK inhibitors can be dramatic and durable, duration of response may eventually be limited by acquired resistance via several mechanisms, including resistance mutations such as NTRK1-G595R. Repotrectinib is a second-generation TRK inhibitor, which is active against NTRK1-G595R. However, its efficacy against entrectinib-resistant tumors has not been fully elucidated. In the present study, we established entrectinib-resistant tumor cells (M3B) in a brain metastasis model inoculated with NTRK1-rearranged KM12SM cells, and examined the sensitivity of M3B cells to repotrectinib. While M3B cells harbored the NTRK1-G595R mutation, they were unexpectedly resistant to repotrectinib. The resistance was due to extracellular signal-regulated kinase (ERK) reactivation partially mediated by epidermal growth factor receptor (EGFR) activation. We further demonstrate that the triplet combination of repotrectinib, EGFR inhibitor, and MEK inhibitor could sensitize M3B cells in vitro as well as in a brain metastasis model. These results indicate that resistant mutations, such as NTRK1-G595R, and alternative pathway activation, such as ERK activation, could simultaneously occur in entrectinib-resistant tumors, thereby causing resistance to second-generation inhibitor repotrectinib. These findings highlight the importance of intensive examinations to identify resistance mechanisms and application of the appropriate combination treatment to circumvent the resistance.

DOI： 10.1111/cas.15354

PubMed

researchmap

掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/hep.32573

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Mosby Inc.  

DOI： 10.1016/j.oooo.2021.03.020

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We investigated whether early circulating tumor DNA (ctDNA) changes, measured using digital PCR (dPCR), can predict later chemotherapy responses in esophageal squamous cell cancer (ESCC). We compared the dynamics of ctDNA and tumor volumes during chemotherapy in 42 ESCC. The accuracy of predictions of later chemotherapy responses were evaluated by the ratio of the variant allele frequency (VAF) of ctDNA (post-/pre-ctDNA) and the total tumor volume (post-/pre-volume) before and after an initial chemotherapy cycle using a receiver-operating characteristic curve analysis. Total positive and negative objective responses (ORs) were defined as either >50% or ≤50% reductions, respectively, in the total tumor volume at the end of first-line chemotherapy. Mutation screening of 43 tumors from 42 patients revealed 96 mutations. The pretreatment dPCR-ctDNA data were informative in 38 patients, using 70 selected mutations (1-3 per patient). The areas under the curve (AUCs) for the post-/pre-volume and post-/pre-ctDNA levels used in predicting the total OR were 0.85 and 0.88, respectively. The optimal cutoff value of post-/pre-ctDNA was 0.13. In 20 patients with post-/pre-volume ≥50%, the total OR could be predicted by the post-/pre-ctDNA with high accuracy; the AUC by post-/pre-ctDNA was higher than that by post-/pre-volume (0.85 vs 0.76, respectively). Patients with low post-/pre-ctDNA (n = 18) had a significantly better overall survival rate than those with high post-/pre-ctDNA (n = 20; P = 0.03). Early ctDNA changes after an initial cycle of chemotherapy predict later responses to treatment with high accuracy in ESCC patients.

DOI： 10.1093/carcin/bgab088

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We often encounter situations in which data from the TCGA that have been analyzed in papers we read or reviewed cannot be reproduced, even when TCGA datasets are used, especially in survival analyses. Therefore, we attempted to confirm the data source for TCGA survival analysis and found that several websites used to analyze the survival data of TCGA datasets inappropriately handle the survival data, causing differences in statistical analyses. This causes the misinterpretation of results because figures of survival analysis results in several papers are sometimes exactly as generated by these sites, and the results depend on only the tools provided by these sites. We would like to make this situation widely known and raise the problem for scientific soundness.

DOI： 10.1080/15384047.2021.1979845

PubMed

researchmap

掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/1346-8138.15919

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

A disintegrin and metalloprotease 17 (ADAM17) is the major sheddase that processes more than 80 substrates, including tumour necrosis factor-α (TNFα). The homozygous genetic deficiency of ADAM17 causing a complete loss of ADAM17 expression was reported to be linked to neonatal inflammatory skin and bowel disease 1 (NISBD1). Here we report for the first time, a family with NISBD1 caused by functionally confirmed compound heterozygous missense variants of ADAM17, namely c.1699T>C (p.Cys567Arg) and c.1799G>A (p.Cys600Tyr). Both variants were detected in two siblings with clinical features of NISBD1, such as erythroderma with exudate in whole body, recurrent skin infection and sepsis and prolonged diarrhoea. In a cell-based assay using Adam10/17 double-knockout mouse embryonic fibroblasts (Adam10/17-/- mEFs) exogenously expressing each of these mutants, phorbol 12-myristate 13-acetate-stimulated shedding was strongly reduced compared with wild-type ADAM17. Thus, in vitro functional assays demonstrated that both missense variants cause the loss-of-function of ADAM17, resulting in the development of NISBD1. Our study further expands the spectrum of genetic pathology underlying ADAM17 in NISBD1 and establishes functional assay systems for its missense variants.

DOI： 10.1038/s41598-021-89063-0

PubMed

researchmap

掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

<title>Abstract</title>
The aggressive invasiveness of malignant mesothelioma limits cancer therapy, however, the molecular mechanisms underlying the invasiveness remain largely unknown. Here we found that the matrix metalloproteinase-2 (MMP-2) was required for the invasion of mesothelioma cells in the collagen matrix and the gene expression of MMP-2 was correlated with the invasive phenotype. The MMP-2 gene expression was regulated by DNA and histone methylation around the transcription start site, implicating the involvement of the polycomb repressive complex (PRC). Knockdown of PRC component chromobox 6 (CBX6) promoted MMP-2 expression and invasion of mesothelioma cells. Transcriptome analysis suggested that CBX6 regulates sets of genes involved in cancer cell migration and metastasis. In invasive but not non-invasive cells, CBX6 was constantly unstable owing to ubiquitination and protein degradation. In human tissues, CBX6 localized in the nuclei of normal mesothelium and benign mesothelioma, but the nuclear staining of CBX6 was lost in malignant mesothelioma. These results suggest involvement of proteasomal degradation of CBX6 in mesothelioma progression.

その他リンク： http://www.nature.com/articles/s41598-020-72448-y

DOI： 10.1038/s41598-020-72448-y

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: We aimed to identify novel tumor-promoting drivers highly expressed in gastric cancer (GC) that contribute to worsened prognosis in affected patients. METHODS: Genes whose expression was increased and correlated with worse prognosis in GC were screened using datasets from the Cancer Genome Atlas and Gene Expression Omnibus. We examined Claudin-6 (CLDN6) immunoreactivity in GC tissues and the effect of CLDN6 on cellular functions in GC cell lines. The mechanisms underlying GC-promoting function of CLDN6 were also investigated. RESULTS: CLDN6 was identified as a gene overexpressed in GC tumors as compared with adjacent non-tumorous tissues and whose increased expression was positively correlated with worse overall survival of GC patients, particularly those with Lauren's intestinal type GC, in data from multiple publicly available datasets. Additionally, membranous CLDN6 immunoreactivity detected in intestinal type GC tumors was correlated with worse overall survival. In CLDN6-expressing GC cells, silencing of CLDN6 inhibited cell proliferation and migration/invasion abilities, possibly via suppressing transcription of YAP1 and its downstream transcriptional targets at least in part. CONCLUSIONS: This study identified CLDN6 as a GC-promoting gene, suggesting that CLDN6 to be a possible single prognostic marker and promising therapeutic target for a subset of GC patients.

DOI： 10.1007/s10120-019-01014-x

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

p53 is one of the most important tumor suppressor genes, and the exploration of p53-target genes is important for elucidation of its functional mechanisms. In this study, we identified Armadillo Repeat gene deleted in Velo-Cardio-Facial syndrome (ARVCF) as a direct target of p53 through ChIP-sequencing analysis. Activated p53 protein was found to bind to two distinct sites in the ARVCF gene, resulting in induction of ARVCF expression at both the mRNA and protein levels. We revealed that the knockdown of ARVCF inhibited p53-induced apoptosis. Interestingly, ARVCF interacted with hnRNPH2, which is involved in pre-mRNA splicing, and ARVCF knockdown induced dynamic changes in alternative splicing patterns. These results suggest that p53-induced ARVCF indirectly, but not directly, regulates p53 target selectivity through splicing alterations of specific genes. Thus, we demonstrated that the induction of ARVCF expression contributed to the tumor suppressive function of p53. Recently, it has been reported that many tumors have thousands of alternative splicing events that are not detectable in normal samples. ARVCF may play a role in alternative splicing events in cancer and may provide clues to explore novel approaches for cancer diagnosis and therapy.

DOI： 10.1038/s41388-019-1133-7

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/15384047.2019.1702406

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12885-019-5715-0

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/cam4.2345

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Association for Cancer Research ({AACR})  

DOI： 10.1158/0008-5472.CAN-18-3604

PubMed

researchmap

掲載種別：研究論文（学術雑誌）  

DOI： 10.1099/jgv.0.001250

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1158/2159-8290.CD-18-0689

PubMed

researchmap

記述言語：日本語   出版者・発行元：(株)ニュー・サイエンス社  

医中誌

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ccell.2018.08.009

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Purpose: Rearrangement of the neurotrophic tropomyosin receptor kinase 1 (NTRK1) gene, which encodes tyrosine receptor kinase A (TRK-A), occurs in various cancers, including colon cancer. Although entrectinib is effective in the treatment of central nervous system (CNS) metastases that express NTRK1 fusion proteins, acquired resistance inevitably results in recurrence. The CNS is a sanctuary for targeted drugs; however, the mechanism by which CNS metastases become entrectinib-resistant remains elusive and must be clarified to develop better therapeutics.Experimental Design: The entrectinib-resistant cell line KM12SM-ER was developed by continuous treatment with entrectinib in the brain metastasis-mimicking model inoculated with the entrectinib-sensitive human colon cancer cell line KM12SM, which harbors the TPM3-NTRK1 gene fusion. The mechanism of entrectinib resistance in KM12SM-ER cells was examined by next-generation sequencing. Compounds that overcame entrectinib resistance were screened from a library of 122 kinase inhibitors.Results: KM12SM-ER cells, which showed moderate resistance to entrectinib in vitro, had acquired the G667C mutation in NTRK1 The kinase inhibitor foretinib inhibited TRK-A phosphorylation and the viability of KM12SM-ER cells bearing the NTRK1-G667C mutation in vitro Moreover, foretinib markedly inhibited the progression of entrectinib-refractory KM12SM-ER-derived liver metastases and brain tumors in animal models, predominantly through inhibition of TRK-A phosphorylation.Conclusions: These results suggest that foretinib may be effective in overcoming entrectinib resistance associated with the NTRK1-G667C mutation in NTRK1 fusion-positive tumors in various organs, including the brain, and provide a rationale for clinical trials of foretinib in cancer patients with entrectinib-resistant tumors harboring the NTRK1-G667C mutation, including patients with brain metastases. Clin Cancer Res; 24(10); 2357-69. ©2018 AACR.

DOI： 10.1158/1078-0432.CCR-17-1623

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Rett syndrome (RTT) is a severe neurodevelopmental disorder typically affecting females. It is mainly caused by loss-of-function mutations that affect the coding sequence of exon 3 or 4 of methyl-CpG-binding protein 2 (MECP2). Severe neonatal encephalopathy resulting in death before the age of 2 years is the most common phenotype observed in males affected by a pathogenic MECP2 variant. Mutations in MECP2 exon 1 affecting the MeCP2_e1 isoform are relatively rare causes of RTT in females, and only one case of a male patient with MECP2-related severe neonatal encephalopathy caused by a mutation in MECP2 exon 1 has been reported. This is the first reported case of a male with classic RTT caused by a 5-bp duplication in the open-reading frame of MECP2 exon 1 (NM_001110792.1:c.23_27dup) that introduced a premature stop codon [p.(Ser10Argfs*36)] in the MeCP2_e1 isoform, which has been reported in one female patient with classic RTT. Therefore, both males and females displaying at least some type of MeCP2_e1 mutation may exhibit the classic RTT phenotype.

DOI： 10.1002/ajmg.a.38595

PubMed

researchmap

記述言語：英語   出版者・発行元：Wiley  

Molecular-targeted drugs are generally effective against tumors containing driver oncogenes, such as EGFR, ALK, and NTRK1. However, patients harboring these oncogenes frequently experience a progression of brain metastases during treatment. Here, we present an in vivo imaging model for brain tumors using human cancer cell lines, including the EGFR-L858R/T790M-positive H1975 lung adenocarcinoma cells, the NUGC4 hepatocyte growth factor (HGF)-dependent gastric cancer cells, and the KM12SM colorectal cancer cells containing the TPM3-NTRK1 gene fusion. We investigated the efficacy of targeted drugs by comparison with their effect in extracranial models. In vitro, H1975 cells were sensitive to the third-generation epidermal growth factor receptor inhibitor osimertinib. Moreover, HGF stimulated the proliferation of NUGC4 cells, that was inhibited by crizotinib, which has anti-MET activity. KM12SM cells were sensitive to the tropomyosin-related kinase-A inhibitors crizotinib and entrectinib. In in vivo H1975 cell models, osimertinib inhibited the progression of both brain and subcutaneous tumors. Furthermore, in in vivo NUGC4 cell models, crizotinib remarkably delayed the progression of brain tumors, and that of peritoneal carcinomatosis. Interestingly, in in vivo KM12SM cell models, treatment with crizotinib delayed the progression of liver metastases, but not that of brain tumors. Conversely, treatment with entrectinib discernibly delayed the progression of both tumor types. Thus, the effect of targeted drugs against brain tumors can differ from the one reported in extracranial tumors. Moreover, the same multikinase inhibitory drug can display different efficacies in brain tumor models containing different drivers. Therefore, our in vivo imaging model for brain tumors may prove useful for preclinical drug screening against brain metastases.

DOI： 10.1002/cam4.1255

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

KH-type splicing regulatory protein (KHSRP) is a multifunctional RNA-binding protein, which is involved in several post-transcriptional aspects of RNA metabolism, including microRNA (miRNA) biogenesis. It affects distinct cell functions in different tissues and can have an impact on various pathological conditions. In the present study, we investigated the oncogenic functions of KHSRP and their underlying mechanisms in the pathogenesis of esophageal squamous cell carcinoma (ESCC). KHSRP expression levels were elevated in ESCC tumors when compared with those in non-tumorous tissues by immunohistochemistry, and cytoplasmic KHSRP overexpression was found to be an independent prognosticator for worse overall survival in a cohort of 104 patients with ESCC. KHSRP knockdown inhibited growth, migration, and invasion of ESCC cells. KHSRP knockdown also inhibited the maturation of cancer-associated miRNAs, such as miR-21, miR-130b, and miR-301, and induced the expression of their target mRNAs, such as BMP6, PDCD4, and TIMP3, resulting in the inhibition of epithelial-to-mesenchymal transition. Our findings uncover a novel oncogenic function of KHSRP in esophageal tumorigenesis and implicate its use as a marker for prognostic evaluation and as a putative therapeutic target in ESCC.

DOI： 10.18632/oncotarget.20926

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2152/jmi.64.233

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.biochi.2016.01.005

PubMed

Web of Science

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/1348-0421.12317

PubMed

Web of Science

researchmap

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0115684

PubMed

Web of Science

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbrc.2014.09.082

PubMed

Web of Science

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Histone methylation is implicated in various biological and pathological processes including cancer development. In this study, we discovered that ectopic expression of KDM5B, a histone H3 lysine 4 (H3K4) demethylase, promoted epithelial-mesenchymal transition (EMT) of cancer cells. KDM5B increased the expression of transcription factors, ZEB1 and ZEB2, followed by downregulation of E-cadherin and upregulation of mesenchymal marker genes. The expression of the microRNA-200 (miR-200) family, which specifically targets ZEB1 and ZEB2, was reduced in the cells with KDM5B overexpression. We found that KDM5B repressed the expression of the miR-200 family by changing histone H3 methylation status of their regulatory regions. The introduction of miR-200 precursor in the cells inhibited EMT induction by KDM5B, suggesting that miR-200 family was a critical downstream mediator of KDM5B-promoted EMT. Furthermore, knockdown of KDM5B was shown to affect the expression of EMT-related genes, indicating the involvement of endogenous KDM5B. Our study demonstrated a novel role of KDM5B histone lysine demethylase in EMT, which may contribute to malignant progression of cancer.

DOI： 10.4161/cc.25142

PubMed

researchmap

掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1111/cas.12169

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/1743-422X-10-153

PubMed

Web of Science

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.virusres.2011.02.001

PubMed

Web of Science

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbrc.2009.06.082

PubMed

Web of Science

researchmap

記述言語：英語   出版者・発行元：生命科学系学会合同年次大会運営事務局  

医中誌

researchmap

記述言語：英語   出版者・発行元：生命科学系学会合同年次大会運営事務局  

医中誌

researchmap

記述言語：日本語   出版者・発行元：生命科学系学会合同年次大会運営事務局  

医中誌

researchmap

記述言語：日本語   出版者・発行元：生命科学系学会合同年次大会運営事務局  

医中誌

researchmap

記述言語：英語   出版者・発行元：生命科学系学会合同年次大会運営事務局  

医中誌

researchmap

記述言語：英語   出版者・発行元：日本癌学会  

医中誌

researchmap

記述言語：英語   出版者・発行元：日本癌学会  

医中誌

researchmap

記述言語：英語   出版者・発行元：日本癌学会  

医中誌

researchmap

記述言語：英語   出版者・発行元：日本癌学会  

医中誌

researchmap