Genome‑wide DNA hypomethylation drives a more invasive pancreatic cancer phenotype and has predictive occult distant metastasis and prognosis potential
Genome‑wide DNA hypomethylation is the most common molecular feature in human cancers associated with chromosomal instability (CIN), which is involved in the mechanisms that regulate pancreatic cancer (PC) metastasis. It was investigated whether genome‑wide DNA hypomethylation affects the phenotype...
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Veröffentlicht in: | International journal of oncology 2022-06, Vol.60 (6), p.1, Article 61 |
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creator | Endo, Yuhei Suzuki, Koichi Kimura, Yasuaki Tamaki, Sawako Aizawa, Hidetoshi Abe, Iku Watanabe, Fumiaki Kato, Takaharu Saito, Masaaki Futsuhara, Kazushige Noda, Hiroshi Konishi, Fumio Rikiyama, Toshiki |
description | Genome‑wide DNA hypomethylation is the most common molecular feature in human cancers associated with chromosomal instability (CIN), which is involved in the mechanisms that regulate pancreatic cancer (PC) metastasis. It was investigated whether genome‑wide DNA hypomethylation affects the phenotype in PC via CIN
, and its significance on the biological behavior of PC was verified. The relative demethylation level (RDL) of long interspersed nucleotide element‑1 (LINE‑1) in human PC cell lines was used to characterize DNA hypomethylation using methylation‑specific quantitative (q)PCR. CIN was estimated by changes in chromosomal copy number using comparative genomic hybridization analysis. Abnormal segregation of chromosomes was assessed by immunocytochemistry, and the DNA damage response was evaluated using the number of anti‑γH2AX positive cells. Invasion ability was assessed using a Matrigel invasion assay. Clinical specimens from 49 patients with PC who underwent curative surgery were evaluated for a correlation of DNA hypomethylation with clinical outcome. Successful induction of genome‑wide DNA hypomethylation in PC cells led to copy number changes in specific chromosomal regions. The number of cells with abnormal segregation of chromosomes significantly increased with the number of anti‑γH2AX positive cells. The invasive potential of these cells also significantly increased. The occurrence of occult distant metastasis in the clinical specimens and receiver operating characteristic analysis clearly identified those who were and were not likely to have occult distant metastasis, with high LINE‑1 RDL significantly correlated with the presence of occult distant metastasis (P=0.035) and poor prognosis (P=0.048). The significance of genome‑wide DNA hypomethylation on the biological behavior of PC, which promotes a more invasive phenotype via CIN
and predicts the susceptibility to occult distant metastasis and poor prognosis in patients with PC was revealed. |
doi_str_mv | 10.3892/ijo.2022.5351 |
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, and its significance on the biological behavior of PC was verified. The relative demethylation level (RDL) of long interspersed nucleotide element‑1 (LINE‑1) in human PC cell lines was used to characterize DNA hypomethylation using methylation‑specific quantitative (q)PCR. CIN was estimated by changes in chromosomal copy number using comparative genomic hybridization analysis. Abnormal segregation of chromosomes was assessed by immunocytochemistry, and the DNA damage response was evaluated using the number of anti‑γH2AX positive cells. Invasion ability was assessed using a Matrigel invasion assay. Clinical specimens from 49 patients with PC who underwent curative surgery were evaluated for a correlation of DNA hypomethylation with clinical outcome. Successful induction of genome‑wide DNA hypomethylation in PC cells led to copy number changes in specific chromosomal regions. The number of cells with abnormal segregation of chromosomes significantly increased with the number of anti‑γH2AX positive cells. The invasive potential of these cells also significantly increased. The occurrence of occult distant metastasis in the clinical specimens and receiver operating characteristic analysis clearly identified those who were and were not likely to have occult distant metastasis, with high LINE‑1 RDL significantly correlated with the presence of occult distant metastasis (P=0.035) and poor prognosis (P=0.048). The significance of genome‑wide DNA hypomethylation on the biological behavior of PC, which promotes a more invasive phenotype via CIN
and predicts the susceptibility to occult distant metastasis and poor prognosis in patients with PC was revealed.</description><identifier>ISSN: 1019-6439</identifier><identifier>EISSN: 1791-2423</identifier><identifier>DOI: 10.3892/ijo.2022.5351</identifier><identifier>PMID: 35419613</identifier><language>eng</language><publisher>Greece: Spandidos Publications</publisher><subject>Antigens ; Biomarkers ; Biotechnology industry ; Cancer ; Cancer therapies ; Cell culture ; Chemotherapy ; Chromosomal Instability - genetics ; Chromosomes ; Comparative Genomic Hybridization ; Cytogenetics ; Development and progression ; DNA ; DNA Methylation ; DNA repair ; Electronics industry ; Epigenetics ; Genetic aspects ; Genomes ; Genomics ; Humans ; Instrument industry ; Medical prognosis ; Metastasis ; Methylation ; Pancreatic cancer ; Pancreatic Neoplasms ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - surgery ; Patients ; Phenotype ; Prognosis ; Scientific equipment and supplies industry ; Surgery ; Thermal cycling ; Tumors</subject><ispartof>International journal of oncology, 2022-06, Vol.60 (6), p.1, Article 61</ispartof><rights>COPYRIGHT 2022 Spandidos Publications</rights><rights>Copyright Spandidos Publications UK Ltd. 2022</rights><rights>Copyright: © Endo et al. 2022</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c579t-2cba9ec9ac5c14a77c3af1688de887c2405fcdec92a2a326eefd3c472d0f4db83</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35419613$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Endo, Yuhei</creatorcontrib><creatorcontrib>Suzuki, Koichi</creatorcontrib><creatorcontrib>Kimura, Yasuaki</creatorcontrib><creatorcontrib>Tamaki, Sawako</creatorcontrib><creatorcontrib>Aizawa, Hidetoshi</creatorcontrib><creatorcontrib>Abe, Iku</creatorcontrib><creatorcontrib>Watanabe, Fumiaki</creatorcontrib><creatorcontrib>Kato, Takaharu</creatorcontrib><creatorcontrib>Saito, Masaaki</creatorcontrib><creatorcontrib>Futsuhara, Kazushige</creatorcontrib><creatorcontrib>Noda, Hiroshi</creatorcontrib><creatorcontrib>Konishi, Fumio</creatorcontrib><creatorcontrib>Rikiyama, Toshiki</creatorcontrib><title>Genome‑wide DNA hypomethylation drives a more invasive pancreatic cancer phenotype and has predictive occult distant metastasis and prognosis potential</title><title>International journal of oncology</title><addtitle>Int J Oncol</addtitle><description>Genome‑wide DNA hypomethylation is the most common molecular feature in human cancers associated with chromosomal instability (CIN), which is involved in the mechanisms that regulate pancreatic cancer (PC) metastasis. It was investigated whether genome‑wide DNA hypomethylation affects the phenotype in PC via CIN
, and its significance on the biological behavior of PC was verified. The relative demethylation level (RDL) of long interspersed nucleotide element‑1 (LINE‑1) in human PC cell lines was used to characterize DNA hypomethylation using methylation‑specific quantitative (q)PCR. CIN was estimated by changes in chromosomal copy number using comparative genomic hybridization analysis. Abnormal segregation of chromosomes was assessed by immunocytochemistry, and the DNA damage response was evaluated using the number of anti‑γH2AX positive cells. Invasion ability was assessed using a Matrigel invasion assay. Clinical specimens from 49 patients with PC who underwent curative surgery were evaluated for a correlation of DNA hypomethylation with clinical outcome. Successful induction of genome‑wide DNA hypomethylation in PC cells led to copy number changes in specific chromosomal regions. The number of cells with abnormal segregation of chromosomes significantly increased with the number of anti‑γH2AX positive cells. The invasive potential of these cells also significantly increased. The occurrence of occult distant metastasis in the clinical specimens and receiver operating characteristic analysis clearly identified those who were and were not likely to have occult distant metastasis, with high LINE‑1 RDL significantly correlated with the presence of occult distant metastasis (P=0.035) and poor prognosis (P=0.048). The significance of genome‑wide DNA hypomethylation on the biological behavior of PC, which promotes a more invasive phenotype via CIN
and predicts the susceptibility to occult distant metastasis and poor prognosis in patients with PC was revealed.</description><subject>Antigens</subject><subject>Biomarkers</subject><subject>Biotechnology industry</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Cell culture</subject><subject>Chemotherapy</subject><subject>Chromosomal Instability - genetics</subject><subject>Chromosomes</subject><subject>Comparative Genomic Hybridization</subject><subject>Cytogenetics</subject><subject>Development and progression</subject><subject>DNA</subject><subject>DNA Methylation</subject><subject>DNA repair</subject><subject>Electronics industry</subject><subject>Epigenetics</subject><subject>Genetic aspects</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Humans</subject><subject>Instrument industry</subject><subject>Medical prognosis</subject><subject>Metastasis</subject><subject>Methylation</subject><subject>Pancreatic cancer</subject><subject>Pancreatic Neoplasms</subject><subject>Pancreatic Neoplasms - genetics</subject><subject>Pancreatic Neoplasms - surgery</subject><subject>Patients</subject><subject>Phenotype</subject><subject>Prognosis</subject><subject>Scientific equipment and supplies industry</subject><subject>Surgery</subject><subject>Thermal cycling</subject><subject>Tumors</subject><issn>1019-6439</issn><issn>1791-2423</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNptkstuFDEQRVsIREJgyRZZQmLXgx_98gYpChCQItjA2qqxq6c96rYb2zPR7PgFlvweX4KbhJCRkBcul0_d8uMWxXNGV6KT_LXd-hWnnK9qUbMHxSlrJSt5xcXDHFMmy6YS8qR4EuOWUl7XlD0uTkRdMdkwcVr8vETnJ_z1_ce1NUjefjonw2HOmTQcRkjWO2KC3WMkQCYfkFi3h5gTZAanA2ZEE51DDGQeslY6zEjAGTJAJHNAY3VacK_1bkzE2JjAJZIbQI6ijX_gOfiN88tq9gldsjA-LR71MEZ8djufFV_fv_ty8aG8-nz58eL8qtR1K1PJ9Rokagm61qyCttUCetZ0ncGuazWvaN1rkwEOHARvEHsjdNVyQ_vKrDtxVry50Z136wmNzt0DjGoOdoJwUB6sOt5xdlAbv1eSsppJmgVe3goE_22HMamt3wWXz6x40wjRNRXt_lEbGFFZ1_sspicbtTpvab5Kx2uZqdV_qDwMTlZ7h73N-aOCV_cKBoQxDdGPu-Xn4jFY3oA6-BgD9nc3ZFQtTlLZSWpxklqclPkX95_ljv5rHfEbEtXJgA</recordid><startdate>20220601</startdate><enddate>20220601</enddate><creator>Endo, Yuhei</creator><creator>Suzuki, Koichi</creator><creator>Kimura, Yasuaki</creator><creator>Tamaki, Sawako</creator><creator>Aizawa, Hidetoshi</creator><creator>Abe, Iku</creator><creator>Watanabe, Fumiaki</creator><creator>Kato, Takaharu</creator><creator>Saito, Masaaki</creator><creator>Futsuhara, Kazushige</creator><creator>Noda, Hiroshi</creator><creator>Konishi, Fumio</creator><creator>Rikiyama, Toshiki</creator><general>Spandidos Publications</general><general>Spandidos Publications UK Ltd</general><general>D.A. 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genetics</topic><topic>Chromosomes</topic><topic>Comparative Genomic Hybridization</topic><topic>Cytogenetics</topic><topic>Development and progression</topic><topic>DNA</topic><topic>DNA Methylation</topic><topic>DNA repair</topic><topic>Electronics industry</topic><topic>Epigenetics</topic><topic>Genetic aspects</topic><topic>Genomes</topic><topic>Genomics</topic><topic>Humans</topic><topic>Instrument industry</topic><topic>Medical prognosis</topic><topic>Metastasis</topic><topic>Methylation</topic><topic>Pancreatic cancer</topic><topic>Pancreatic Neoplasms</topic><topic>Pancreatic Neoplasms - genetics</topic><topic>Pancreatic Neoplasms - surgery</topic><topic>Patients</topic><topic>Phenotype</topic><topic>Prognosis</topic><topic>Scientific equipment and supplies industry</topic><topic>Surgery</topic><topic>Thermal cycling</topic><topic>Tumors</topic><toplevel>online_resources</toplevel><creatorcontrib>Endo, Yuhei</creatorcontrib><creatorcontrib>Suzuki, Koichi</creatorcontrib><creatorcontrib>Kimura, Yasuaki</creatorcontrib><creatorcontrib>Tamaki, Sawako</creatorcontrib><creatorcontrib>Aizawa, Hidetoshi</creatorcontrib><creatorcontrib>Abe, Iku</creatorcontrib><creatorcontrib>Watanabe, Fumiaki</creatorcontrib><creatorcontrib>Kato, Takaharu</creatorcontrib><creatorcontrib>Saito, Masaaki</creatorcontrib><creatorcontrib>Futsuhara, Kazushige</creatorcontrib><creatorcontrib>Noda, Hiroshi</creatorcontrib><creatorcontrib>Konishi, Fumio</creatorcontrib><creatorcontrib>Rikiyama, Toshiki</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>British Nursing Database</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>International journal of oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Endo, Yuhei</au><au>Suzuki, Koichi</au><au>Kimura, Yasuaki</au><au>Tamaki, Sawako</au><au>Aizawa, Hidetoshi</au><au>Abe, Iku</au><au>Watanabe, Fumiaki</au><au>Kato, Takaharu</au><au>Saito, Masaaki</au><au>Futsuhara, Kazushige</au><au>Noda, Hiroshi</au><au>Konishi, Fumio</au><au>Rikiyama, Toshiki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genome‑wide DNA hypomethylation drives a more invasive pancreatic cancer phenotype and has predictive occult distant metastasis and prognosis potential</atitle><jtitle>International journal of oncology</jtitle><addtitle>Int J Oncol</addtitle><date>2022-06-01</date><risdate>2022</risdate><volume>60</volume><issue>6</issue><spage>1</spage><pages>1-</pages><artnum>61</artnum><issn>1019-6439</issn><eissn>1791-2423</eissn><abstract>Genome‑wide DNA hypomethylation is the most common molecular feature in human cancers associated with chromosomal instability (CIN), which is involved in the mechanisms that regulate pancreatic cancer (PC) metastasis. It was investigated whether genome‑wide DNA hypomethylation affects the phenotype in PC via CIN
, and its significance on the biological behavior of PC was verified. The relative demethylation level (RDL) of long interspersed nucleotide element‑1 (LINE‑1) in human PC cell lines was used to characterize DNA hypomethylation using methylation‑specific quantitative (q)PCR. CIN was estimated by changes in chromosomal copy number using comparative genomic hybridization analysis. Abnormal segregation of chromosomes was assessed by immunocytochemistry, and the DNA damage response was evaluated using the number of anti‑γH2AX positive cells. Invasion ability was assessed using a Matrigel invasion assay. Clinical specimens from 49 patients with PC who underwent curative surgery were evaluated for a correlation of DNA hypomethylation with clinical outcome. Successful induction of genome‑wide DNA hypomethylation in PC cells led to copy number changes in specific chromosomal regions. The number of cells with abnormal segregation of chromosomes significantly increased with the number of anti‑γH2AX positive cells. The invasive potential of these cells also significantly increased. The occurrence of occult distant metastasis in the clinical specimens and receiver operating characteristic analysis clearly identified those who were and were not likely to have occult distant metastasis, with high LINE‑1 RDL significantly correlated with the presence of occult distant metastasis (P=0.035) and poor prognosis (P=0.048). The significance of genome‑wide DNA hypomethylation on the biological behavior of PC, which promotes a more invasive phenotype via CIN
and predicts the susceptibility to occult distant metastasis and poor prognosis in patients with PC was revealed.</abstract><cop>Greece</cop><pub>Spandidos Publications</pub><pmid>35419613</pmid><doi>10.3892/ijo.2022.5351</doi><oa>free_for_read</oa></addata></record> |
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source | Spandidos Publications Journals; MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
subjects | Antigens Biomarkers Biotechnology industry Cancer Cancer therapies Cell culture Chemotherapy Chromosomal Instability - genetics Chromosomes Comparative Genomic Hybridization Cytogenetics Development and progression DNA DNA Methylation DNA repair Electronics industry Epigenetics Genetic aspects Genomes Genomics Humans Instrument industry Medical prognosis Metastasis Methylation Pancreatic cancer Pancreatic Neoplasms Pancreatic Neoplasms - genetics Pancreatic Neoplasms - surgery Patients Phenotype Prognosis Scientific equipment and supplies industry Surgery Thermal cycling Tumors |
title | Genome‑wide DNA hypomethylation drives a more invasive pancreatic cancer phenotype and has predictive occult distant metastasis and prognosis potential |
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