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Article ; Online: Inhibition of PRMT5/MEP50 Arginine Methyltransferase Activity Causes Cancer Vulnerability in NDRG2

Ichikawa, Tomonaga / Suekane, Akira / Nakahata, Shingo / Iha, Hidekatsu / Shimoda, Kazuya / Murakami, Takashi / Morishita, Kazuhiro

International journal of molecular sciences

2024 Volume 25, Issue 5

Abstract: N-myc downstream-regulated gene 2 (NDRG2), which is a tumour suppressor, is frequently lost in many types of tumours, including adult T-cell leukaemia/lymphoma (ATL). The downregulation of NDRG2 expression is involved in tumour progression through the ... ...

Abstract	N-myc downstream-regulated gene 2 (NDRG2), which is a tumour suppressor, is frequently lost in many types of tumours, including adult T-cell leukaemia/lymphoma (ATL). The downregulation of NDRG2 expression is involved in tumour progression through the aberrant phosphorylation of several important signalling molecules. We observed that the downregulation of NDRG2 induced the translocation of protein arginine methyltransferase 5 (PRMT5) from the nucleus to the cytoplasm via the increased phosphorylation of PRMT5 at Serine 335. In NDRG2
MeSH term(s)	Adult ; Humans ; Protein-Arginine N-Methyltransferases/metabolism ; Leukemia-Lymphoma, Adult T-Cell/pathology ; Adaptor Proteins, Signal Transducing/metabolism ; Arginine/metabolism ; Methylation ; Neoplasms ; Lymphoma ; Tumor Suppressor Proteins/metabolism ; Intracellular Signaling Peptides and Proteins
Chemical Substances	PRMT2 protein, human (EC 2.1.1.319) ; Protein-Arginine N-Methyltransferases (EC 2.1.1.319) ; Adaptor Proteins, Signal Transducing ; Arginine (94ZLA3W45F) ; MEP50 protein, human ; NDRG2 protein, human ; Tumor Suppressor Proteins ; PRMT5 protein, human (EC 2.1.1.319) ; Intracellular Signaling Peptides and Proteins
Language	English
Publishing date	2024-02-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25052842
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Article ; Online: The CGRP Receptor Antagonist MK0974 Induces EVI1

Suekane, Akira / Ichikawa, Tomonaga / Saito, Yusuke / Nakahata, Shingo / Morishita, Kazuhiro

Anticancer research

2022 Volume 42, Issue 10, Page(s) 4743–4752

Abstract: Background/aim: Acute myeloid leukemia (AML) with high expression of the oncogenic transcription factor ecotropic viral integration site-1 (EVI1) (EVI1: Materials and methods: An in vitro experimental system was used to determine the effect of MK0974 ...

Abstract	Background/aim: Acute myeloid leukemia (AML) with high expression of the oncogenic transcription factor ecotropic viral integration site-1 (EVI1) (EVI1 Materials and methods: An in vitro experimental system was used to determine the effect of MK0974 on EVI1 Results: Apoptosis was induced by adding MK0974 to the EVI1 Conclusion: MK0974, a CGRP receptor antagonist, inhibits the CRLR/RAMP1 complex and induces apoptosis, making it a potential therapeutic agent for CRLR/RAMP1
MeSH term(s)	Apoptosis ; Azepines ; Calcitonin Gene-Related Peptide/metabolism ; Calcitonin Gene-Related Peptide/pharmacology ; Calcitonin Gene-Related Peptide Receptor Antagonists ; Calcitonin Receptor-Like Protein ; Humans ; Imidazoles ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Receptor Activity-Modifying Protein 1 ; Receptors, Calcitonin/metabolism ; Transcription Factors/genetics
Chemical Substances	Azepines ; Calcitonin Gene-Related Peptide Receptor Antagonists ; Calcitonin Receptor-Like Protein ; Imidazoles ; Receptor Activity-Modifying Protein 1 ; Receptors, Calcitonin ; Transcription Factors ; telcagepant (D42O649ALL) ; Calcitonin Gene-Related Peptide (JHB2QIZ69Z)
Language	English
Publishing date	2022-10-03
Publishing country	Greece
Document type	Journal Article
ZDB-ID	604549-2
ISSN	1791-7530 ; 0250-7005
ISSN (online)	1791-7530
ISSN	0250-7005
DOI	10.21873/anticanres.15979
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Article ; Online: Pathophysiological significance of N-myc downstream-regulated gene 2 in cancer development through protein phosphatase 2A phosphorylation regulation.

Morishita, Kazuhiro / Nakahata, Shingo / Ichikawa, Tomonaga

Cancer science

2020 Volume 112, Issue 1, Page(s) 22–30

Abstract: N-myc downstream-regulated gene 2 (NDRG2) is a candidate tumor suppressor in various cancers, including adult T-cell leukemia/lymphoma (ATLL). NDRG2, as a stress-responsive protein, is induced by several stress-related signaling pathways and NDRG2 ... ...

Abstract	N-myc downstream-regulated gene 2 (NDRG2) is a candidate tumor suppressor in various cancers, including adult T-cell leukemia/lymphoma (ATLL). NDRG2, as a stress-responsive protein, is induced by several stress-related signaling pathways and NDRG2 negatively regulates various signal transduction pathways. Although it has not been found to function alone, NDRG2 binds serine/threonine protein phosphatase 2A (PP2A), generating a complex that is involved in the regulation of various target proteins. The main function of NDRG2 is to maintain cell homeostasis by suppressing stress-induced signal transduction; however, in cancer, genomic deletions and/or promoter methylation may inhibit the expression of NDRG2, resulting in enhanced tumor development through overactivated signal transduction pathways. A wide variety of tumors develop in Ndrg2-deficient mice, including T-cell lymphoma, liver, lung and other tumors, the characteristics of which are similar to those in Pten-deficient mice. In particular, PTEN is a target molecule of the NDRG2/PP2A complex, which enhances PTEN phosphatase activity by dephosphorylating residues in the PTEN C-terminal region. In ATLL cells, loss of NDRG2 expression leads to the failed recruitment of PP2A to PTEN, resulting in the inactivation of PTEN phosphatase with phosphorylation, ultimately leading to the activation of PI3K/AKT. Thus, NDRG2, as a PP2A adaptor, regulates the global phosphorylation of important signaling molecules. Moreover, the downregulation of NDRG2 expression by long-term stress-induced methylation is directly correlated with the development of ATLL and other cancers. Thus, NDRG2 might be important for the development of stress-induced leukemia and other cancers and has become an important target for novel molecular therapies.
MeSH term(s)	Animals ; Carcinogenesis/genetics ; Humans ; Neoplasms/etiology ; Neoplasms/genetics ; Phosphorylation/genetics ; Protein Phosphatase 2/genetics ; Signal Transduction/genetics ; Tumor Suppressor Proteins/genetics
Chemical Substances	Tumor Suppressor Proteins ; Protein Phosphatase 2 (EC 3.1.3.16)
Language	English
Publishing date	2020-12-03
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2115647-5
ISSN	1349-7006 ; 1349-7006
ISSN (online)	1349-7006
ISSN	1349-7006
DOI	10.1111/cas.14716
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Article ; Online: Inhibition of adult T-cell leukemia cell proliferation by polymerized proanthocyanidin from blueberry leaves through JAK proteolysis.

Ichikawa, Tomonaga / Sugamoto, Kazuhiro / Matsuura, Yasushi / Kunitake, Hisato / Shimoda, Kazuya / Morishita, Kazuhiro

Cancer science

2022 Volume 113, Issue 4, Page(s) 1406–1416

Abstract: We have previously reported that the proanthocyanidin (PAC) fraction of blueberry leaf extract (BB-PAC) inhibits the proliferation of HTLV-1-infected adult T-cell leukemia (ATL) by inducing apoptosis. In the present study, we further analyzed the ... ...

Abstract	We have previously reported that the proanthocyanidin (PAC) fraction of blueberry leaf extract (BB-PAC) inhibits the proliferation of HTLV-1-infected adult T-cell leukemia (ATL) by inducing apoptosis. In the present study, we further analyzed the structure of BB-PAC and elucidated the molecular mechanism underlying the inhibitory function of HTLV-1-infected and ATL cells. After hot water extraction with fractionation with methanol-acetone, BB-PAC was found to be concentrated in fractions 4 to 7 (Fr7). The strongest inhibition of ATL cell growth was observed with Fr7, which contained the highest BB-PAC polymerization degree of 14. The basic structure of BB-PAC is mainly B-type bonds, with A-type bonds (7.1%) and cinchonain I units as the terminal unit (6.1%). The molecular mechanism of cytotoxicity observed around Fr7 against ATL cells was the degradation of JAK1 to 3 and the dephosphorylation of STAT3/5, which occurs by proteasome-dependent proteolysis, confirming that PAC directly binds to heat shock protein 90 (HSP90). JAK degradation was caused by proteasome-dependent proteolysis, and we identified the direct binding of PAC to HSP90. In addition, the binding of cochaperone ATPase homolog 1 (AHA1) to HSP90, which is required for activation of the cofactor HSP90, was inhibited by BB-PAC treatment. Therefore, BB-PAC inhibited the formation of the HSP90/AHA1 complex and promoted the degradation of JAK protein due to HSP90 dysfunction. These results suggest that the highly polymerized PAC component from blueberry leaves has great potential as a preventive and therapeutic agent against HTLV-1-infected and ATL cells.
MeSH term(s)	Adult ; Blueberry Plants/chemistry ; Blueberry Plants/metabolism ; Cell Proliferation ; HSP90 Heat-Shock Proteins/metabolism ; Human T-lymphotropic virus 1 ; Humans ; Leukemia-Lymphoma, Adult T-Cell/drug therapy ; Leukemia-Lymphoma, Adult T-Cell/metabolism ; Polymerization ; Proanthocyanidins ; Proteasome Endopeptidase Complex/metabolism ; Proteolysis
Chemical Substances	HSP90 Heat-Shock Proteins ; Proanthocyanidins ; proanthocyanidin (18206-61-6) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2022-02-13
Publishing country	England
Document type	Journal Article
ZDB-ID	2115647-5
ISSN	1349-7006 ; 1349-7006
ISSN (online)	1349-7006
ISSN	1349-7006
DOI	10.1111/cas.15277
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Article: IMiD/CELMoD-induced growth suppression of adult T-cell leukemia/lymphoma cells

Wang, Yu / Shimosaki, Shunsuke / Ikebe, Emi / Iha, Hidekatsu / Yamamoto, Jun-Ichi / Fife, Nichole / Ichikawa, Tomonaga / Hori, Mitsuo / Ogata, Masao / Tsukamoto, Yoshiyuki / Hijiya, Naoki / Moriyama, Masatsugu / Hagiwara, Shotaro / Kusano, Shuichi / Saito, Masumichi / Ahmed, Kamruddin / Nishizono, Akira / Handa, Hiroshi / Morishita, Kazuhiro

Frontiers in oncology

2024 Volume 13, Page(s) 1272528

Abstract: Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell neoplasia associated with human T-cell leukemia virus type 1 (HTLV-1) infection and has an extremely poor prognosis. Lenalidomide (LEN; a second-generation immunomodulatory drug [IMiD]) has ... ...

Abstract	Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell neoplasia associated with human T-cell leukemia virus type 1 (HTLV-1) infection and has an extremely poor prognosis. Lenalidomide (LEN; a second-generation immunomodulatory drug [IMiD]) has been employed as an additional therapeutic option for ATL since 2017, but its mechanism of action has not been fully proven, and recent studies reported emerging concerns about the development of second primary malignancies in patients treated with long-term IMiD therapy. Our purpose in this study was to elucidate the IMiD-mediated anti-ATL mechanisms. Thirteen ATL-related cell lines were divided into LEN-sensitive or LEN-resistant groups.
Language	English
Publishing date	2024-01-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2023.1272528
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Article ; Online: Antitumor effects of chloroquine/hydroxychloroquine mediated by inhibition of the NF-κB signaling pathway through abrogation of autophagic p47 degradation in adult T-cell leukemia/lymphoma cells.

Fauzi, Yanuar Rahmat / Nakahata, Shingo / Chilmi, Syahrul / Ichikawa, Tomonaga / Nueangphuet, Phawut / Yamaguchi, Ryoji / Nakamura, Tatsufumi / Shimoda, Kazuya / Morishita, Kazuhiro

PloS one

2021 Volume 16, Issue 8, Page(s) e0256320

Abstract: Adult T-cell leukemia/lymphoma (ATLL) originates from human T-cell leukemia virus type 1 (HTLV-1) infection due to the activation of the nuclear factor-κB (NF-κB) signaling pathway to maintain proliferation and survival. An important mechanism of the ... ...

Abstract	Adult T-cell leukemia/lymphoma (ATLL) originates from human T-cell leukemia virus type 1 (HTLV-1) infection due to the activation of the nuclear factor-κB (NF-κB) signaling pathway to maintain proliferation and survival. An important mechanism of the activated NF-κB signaling pathway in ATLL is the activation of the macroautophagy (herafter referred to as autophagy in the remainder of this manuscript)-lysosomal degradation of p47 (NSFL1C), a negative regulator of the NF-κB pathway. Therefore, we considered the use of chloroquine (CQ) or hydroxychloroquine (HCQ) (CQ/HCQ) as an autophagy inhibitor to treat ATLL; these drugs were originally approved by the FDA as antimalarial drugs and have recently been used to treat autoimmune diseases, such as systemic lupus erythematosus (SLE). In this paper, we determined the therapeutic efficacy of CQ/HCQ, as NF-κB inhibitors, in ATLL mediated by blockade of p47 degradation. Administration of CQ/HCQ to ATLL cell lines and primary ATLL cells induced cell growth inhibition in a dose-dependent manner, and the majority of cells underwent apoptosis after CQ administration. As to the molecular mechanism, autophagy was inhibited in CQ-treated ATLL cells, and activation of the NF-κB pathway was suppressed with the restoration of the p47 level. When the antitumor effect of CQ/HCQ was examined using immunodeficient mice transplanted with ATLL cell lines, CQ/HCQ significantly suppressed tumor growth and improved the survival rate in the ATLL xenograft mouse model. Importantly, HCQ selectively induced ATLL cell death in the ATLL xenograft mouse model at the dose used to treat SLE. Taken together, our results suggest that the inhibition of autophagy by CQ/HCQ may become a novel and effective strategy for the treatment of ATLL.
MeSH term(s)	Animals ; Apoptosis ; Autophagy ; Cell Line, Tumor ; Chloroquine/pharmacology ; Gene Expression Regulation, Leukemic ; Human T-lymphotropic virus 1/growth & development ; Human T-lymphotropic virus 1/pathogenicity ; Humans ; Hydroxychloroquine/pharmacology ; Immunologic Factors/pharmacology ; Leukemia-Lymphoma, Adult T-Cell/drug therapy ; Leukemia-Lymphoma, Adult T-Cell/immunology ; Leukemia-Lymphoma, Adult T-Cell/mortality ; Leukemia-Lymphoma, Adult T-Cell/virology ; Male ; Mice ; Mice, SCID ; NF-kappa B/antagonists & inhibitors ; NF-kappa B/genetics ; NF-kappa B/immunology ; Primary Cell Culture ; Signal Transduction/drug effects ; Signal Transduction/genetics ; Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins/genetics ; Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins/immunology ; Survival Analysis ; Xenograft Model Antitumor Assays
Chemical Substances	Immunologic Factors ; NF-kappa B ; Nsfl1c protein, rat ; Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins ; Hydroxychloroquine (4QWG6N8QKH) ; Chloroquine (886U3H6UFF)
Language	English
Publishing date	2021-08-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0256320
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Article ; Online: CGRP-CRLR/RAMP1 signal is important for stress-induced hematopoiesis.

Suekane, Akira / Saito, Yusuke / Nakahata, Shingo / Ichikawa, Tomonaga / Ogoh, Honami / Tsujikawa, Kazutake / Morishita, Kazuhiro

Scientific reports

2019 Volume 9, Issue 1, Page(s) 429

Abstract: Ecotropic viral integration site-1 (EVI1) has a critical role in normal and malignant hematopoiesis. Since we previously identified high expression of calcitonin receptor like receptor (CRLR) in acute myeloid leukemia (AML) with high EVI1 expression, we ... ...

Abstract	Ecotropic viral integration site-1 (EVI1) has a critical role in normal and malignant hematopoiesis. Since we previously identified high expression of calcitonin receptor like receptor (CRLR) in acute myeloid leukemia (AML) with high EVI1 expression, we here characterized the function of CRLR in hematopoiesis. Since higher expression of CRLR and receptor activity modifying protein 1 (RAMP1) was identified in immature hematopoietic bone marrow (BM) cells, we focused on calcitonin gene-related peptide (CGRP), a specific ligand for the CRLR/RAMP1 complex. To elucidate the role of CGRP in hematopoiesis, Ramp1-deficient (Ramp1
MeSH term(s)	Animals ; Apoptosis/genetics ; Apoptosis/immunology ; Bone Marrow/immunology ; Calcitonin Gene-Related Peptide/genetics ; Calcitonin Gene-Related Peptide/immunology ; Calcitonin Receptor-Like Protein/genetics ; Calcitonin Receptor-Like Protein/immunology ; Hematopoiesis/genetics ; Hematopoiesis/immunology ; Mice ; Mice, Knockout ; Reactive Oxygen Species/immunology ; Receptor Activity-Modifying Protein 1/genetics ; Receptor Activity-Modifying Protein 1/immunology ; Signal Transduction/genetics ; Signal Transduction/immunology ; Stress, Physiological/genetics ; Stress, Physiological/immunology
Chemical Substances	Calcitonin Receptor-Like Protein ; Ramp1 protein, mouse ; Reactive Oxygen Species ; Receptor Activity-Modifying Protein 1 ; Calcitonin Gene-Related Peptide (JHB2QIZ69Z)
Language	English
Publishing date	2019-01-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-018-36796-0
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Article ; Online: The regulation of NDRG2 expression during ATLL development after HTLV-1 infection.

Ichikawa, Tomonaga / Nakahata, Shingo / Fujii, Masahiro / Iha, Hidekatsu / Shimoda, Kazuya / Morishita, Kazuhiro

Biochimica et biophysica acta. Molecular basis of disease

2019 Volume 1865, Issue 10, Page(s) 2633–2646

Abstract: N-myc downstream-regulated gene 2 (NDRG2) is a candidate tumor suppressor that is frequently downregulated in adult T-cell leukemia/lymphoma (ATLL) and functions to negatively regulate several cellular signaling pathways as PP2A recruiter. To clarify the ...

Abstract	N-myc downstream-regulated gene 2 (NDRG2) is a candidate tumor suppressor that is frequently downregulated in adult T-cell leukemia/lymphoma (ATLL) and functions to negatively regulate several cellular signaling pathways as PP2A recruiter. To clarify the molecular mechanisms of suppression of NDRG2 expression, we initially determined the expression pattern of NDRG2 in various types of T-cells and ATLL cells. NDRG2 expression was significantly upregulated in HTLV-1/Tax-immortalized T-cells, which was mediated by NF-κB activation through Tax expression. On the other hand, NDRG2 expression was suppressed in HTLV-1-infected cell lines and various types of ATLL cells, which was dependent on the DNA methylation of the NDRG2 promoter. We found that the expression of enhancer of zeste homolog 2 (EZH2), a member of the polycomb family, is increased in ATLL, and that EZH2 directly binds to the NDRG2 promoter and induces DNA methylation of the NDRG2 promoter. Since the expression of EZH2 were anti-parallelly regulated with the NDRG2 expression, EZH2 might be one of the most important regulators of the downregulation of NDRG2, contributing to enhanced activation of signaling pathways during ATLL development.
MeSH term(s)	Adult ; Cell Line, Tumor ; Cell Proliferation ; DNA Methylation ; Down-Regulation ; Enhancer of Zeste Homolog 2 Protein/metabolism ; Gene Expression Regulation, Neoplastic ; HTLV-I Infections/complications ; Human T-lymphotropic virus 1 ; Humans ; Leukemia-Lymphoma, Adult T-Cell/genetics ; Leukemia-Lymphoma, Adult T-Cell/metabolism ; NF-kappa B/metabolism ; Signal Transduction ; T-Lymphocytes ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism ; Up-Regulation
Chemical Substances	NDRG2 protein, human ; NF-kappa B ; Tumor Suppressor Proteins ; EZH2 protein, human (EC 2.1.1.43) ; Enhancer of Zeste Homolog 2 Protein (EC 2.1.1.43)
Language	English
Publishing date	2019-07-08
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-260X ; 1879-2596 ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-260X ; 1879-2596 ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbadis.2019.07.001
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Article ; Online: BCL11B is frequently downregulated in HTLV-1-infected T-cells through Tax-mediated proteasomal degradation.

Permatasari, Happy Kurnia / Nakahata, Shingo / Ichikawa, Tomonaga / Morishita, Kazuhiro

Biochemical and biophysical research communications

2017 Volume 490, Issue 3, Page(s) 1086–1092

Abstract: Human T-cell leukemia virus type 1 (HTLV-1) is a causative agent of adult T-cell leukemia-lymphoma (ATLL). The HTLV-1-encoded protein Tax plays important roles in the proliferation of HTLV-1-infected T-cells by affecting cellular proteins. In this study, ...

Abstract	Human T-cell leukemia virus type 1 (HTLV-1) is a causative agent of adult T-cell leukemia-lymphoma (ATLL). The HTLV-1-encoded protein Tax plays important roles in the proliferation of HTLV-1-infected T-cells by affecting cellular proteins. In this study, we showed that Tax transcriptionally and post-transcriptionally downregulates the expression of the tumor suppressor gene B-cell leukemia/lymphoma 11B (BCL11B), which encodes a lymphoid-related transcription factor. BCL11B expression was downregulated in HTLV-1-infected T-cell lines at the mRNA and protein levels, and forced expression of BCL11B suppressed the proliferation of these cells. The proteasomal inhibitor MG132 increased BCL11B expression in HTLV-1-infected cell lines, and colocalization of Tax with BCL11B was detected in the cytoplasm of HTLV-1-infected T-cells following MG132 treatment. shRNA knock-down of Tax expression also increased the expression of BCL11B in HTLV-1-infected cells. Moreover, we found that Tax physically binds to BCL11B protein and induces the polyubiquitination of BCL11B and proteasome-dependent degradation of BCL11B. Thus, inactivation of BCL11B by Tax protein may play an important role in the Tax-mediated leukemogenesis.
MeSH term(s)	Cell Line, Tumor ; Down-Regulation ; Gene Products, tax/metabolism ; HTLV-I Infections/genetics ; HTLV-I Infections/metabolism ; HTLV-I Infections/virology ; Human T-lymphotropic virus 1/physiology ; Humans ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/virology ; Proteasome Endopeptidase Complex/metabolism ; Proteolysis ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism
Chemical Substances	BCL11B protein, human ; Gene Products, tax ; Repressor Proteins ; Tumor Suppressor Proteins ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2017-08-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2017.06.172
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Article ; Online: Integrin α6A (ITGA6A)-type Splice Variant in Extracellular Vesicles Has a Potential as a Novel Marker of the Early Recurrence of Pancreatic Cancer.

Asada, Takashi / Nakahata, Shingo / Fauzi, Yanuar Rahmat / Ichikawa, Tomonaga / Inoue, Kentaro / Shibata, Nobuhiro / Fujii, Yoshiro / Imamura, Naoya / Hiyoshi, Masahide / Nanashima, Atsushi / Morishita, Kazuhiro

Anticancer research

2022 Volume 42, Issue 4, Page(s) 1763–1775

Abstract: Background/aim: Pancreatic ductal adenocarcinoma (PDAC) is one of the most common cancers worldwide, with a poor prognosis. Owing to the difficulty of early diagnosis, the aim of this study was to isolate biomarkers from extracellular vesicles (EVs) ... ...

Abstract	Background/aim: Pancreatic ductal adenocarcinoma (PDAC) is one of the most common cancers worldwide, with a poor prognosis. Owing to the difficulty of early diagnosis, the aim of this study was to isolate biomarkers from extracellular vesicles (EVs) that can lead to early diagnosis. Materials and methods: EVs in the culture supernatant were isolated from a pancreatic cancer cell line (PK-1) and expanded by using two-dimensional gel electrophoresis, and protein identification from each spot was performed by using matrix-assisted laser desorption ionization mass spectrometry. The identified proteins were classified and compared with previously reported results for EVs from murine pancreatic cancer PAN02 cells, and their expression specificity was examined using PDAC cell lines and patient-derived PDAC tissues. In addition, the significance of selected biomarker(s) was examined based on the changes in biomarkers in the blood EVs of PDAC patients after surgery. Results: We found that the ITGA6A splice variant was predominantly expressed in several pancreatic cancer cell lines and blood EVs from patients with PDAC, whereas the ITGA6B splice variant was predominantly expressed in EVs from the blood of normal volunteers. In the expression pattern of ITGA6 in EVs from blood samples of two PDAC patients before and after resection surgery, the expression of ITGA6A in EVs significantly decreased after surgery and increased several months before clinical recurrence. Furthermore, the increased expression of ITGA6A in EVs occurred much earlier than that of CA19-9. Conclusion: Determination of ITGA6A expression in blood EVs in PDAC patients could be a useful blood marker for the early diagnosis of PDAC recurrence.
MeSH term(s)	Animals ; CA-19-9 Antigen ; Carcinoma, Pancreatic Ductal/diagnosis ; Carcinoma, Pancreatic Ductal/genetics ; Extracellular Vesicles/genetics ; Humans ; Integrin alpha6/genetics ; Mice ; Neoplasm Recurrence, Local ; Pancreatic Neoplasms/diagnosis ; Pancreatic Neoplasms/genetics
Chemical Substances	CA-19-9 Antigen ; ITGA6 protein, human ; Integrin alpha6
Language	English
Publishing date	2022-04-06
Publishing country	Greece
Document type	Journal Article
ZDB-ID	604549-2
ISSN	1791-7530 ; 0250-7005
ISSN (online)	1791-7530
ISSN	0250-7005
DOI	10.21873/anticanres.15653
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