PSMB8 as a Candidate Marker of Responsiveness to Preoperative Radiation Therapy in Rectal Cancer Patients
The ability to predict individual responsiveness to cancer therapy is urgently needed. This is particularly true for patients with locally advanced rectal cancer (LARC) because a large proportion are resistant to preoperative chemoradiation therapy (CRT). In this study, we sought to identify markers...
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| Veröffentlicht in: | International journal of radiation oncology, biology, physics biology, physics, 2017-08, Vol.98 (5), p.1164-1173 |
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| creator | Ha, Ye Jin Tak, Ka Hee Kim, Chan Wook Roh, Seon Ae Choi, Eun Kyung Cho, Dong Hyung Kim, Jeong Hwan Kim, Seon Kyu Kim, Seon Young Kim, Yong Sung Kim, Jin Cheon |
| description | The ability to predict individual responsiveness to cancer therapy is urgently needed. This is particularly true for patients with locally advanced rectal cancer (LARC) because a large proportion are resistant to preoperative chemoradiation therapy (CRT). In this study, we sought to identify markers that could predict response by comparing the gene expression profiles of the tumors of patients who received preoperative CRT.
The basal gene expression profiles of tumors from 22 LARC patients who were responders (n=9) and nonresponders (n=13) to preoperative CRT were analyzed using RNA sequencing (RNA-Seq). To validate the RNA-Seq findings, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was performed on tumor samples from an additional 40 LARC patients (n=20 responders; n=20 nonresponders). Candidate genes were stably overexpressed or knocked down in colorectal cancer (CRC) cell lines, and the effect on response to radiation was tested in vitro and also in vivo in a mouse xenograft model.
Eight differentially expressed (>16-fold) genes (B3GALT4, HSPA1B, KRBOX1, PPBP, PPP1R18, PSMB8, SLC39A7, and TAP2) associated with the preoperative CRT response were identified (P |
| doi_str_mv | 10.1016/j.ijrobp.2017.03.023 |
| format | Article |
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The basal gene expression profiles of tumors from 22 LARC patients who were responders (n=9) and nonresponders (n=13) to preoperative CRT were analyzed using RNA sequencing (RNA-Seq). To validate the RNA-Seq findings, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was performed on tumor samples from an additional 40 LARC patients (n=20 responders; n=20 nonresponders). Candidate genes were stably overexpressed or knocked down in colorectal cancer (CRC) cell lines, and the effect on response to radiation was tested in vitro and also in vivo in a mouse xenograft model.
Eight differentially expressed (>16-fold) genes (B3GALT4, HSPA1B, KRBOX1, PPBP, PPP1R18, PSMB8, SLC39A7, and TAP2) associated with the preoperative CRT response were identified (P<.0005). Among these genes, real-time RT-PCR showed that PSMB8 and SLC39A7 were upregulated in the responsive group of the additional 40 LARC patients. In CRC cell lines, PSMB8 overexpression significantly reduced colony formation and increased the apoptosis-inducing molecules cleaved caspase-3 and cleaved PARP after 6-Gy irradiation. PSMB8 knockdown increased colony formation and decreased caspase-3 activation and cleaved PARP levels after irradiation. SLC39A7 overexpression had no significant effects on irradiated CSC cells. After irradiation of the xenografted mice, tumors that arose from CRC cell line HCT116 overexpressing PSMB8 grew more slowly than did those from HCT116 with vector alone.
These results suggest that PSMB8 is a predictive marker of preoperative radiosensitivity in LARC patients. Clinical validation in a larger cohort is now required.</description><identifier>ISSN: 0360-3016</identifier><identifier>EISSN: 1879-355X</identifier><identifier>DOI: 10.1016/j.ijrobp.2017.03.023</identifier><identifier>PMID: 28721901</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Biomarkers, Tumor - genetics ; Biomarkers, Tumor - metabolism ; Caspase 3 - genetics ; Caspase 3 - metabolism ; Cation Transport Proteins - genetics ; Cation Transport Proteins - metabolism ; Cell Death ; Cell Line, Tumor ; Gene Expression Profiling - methods ; Gene Knockdown Techniques ; Gene Silencing ; Genetic Markers ; Heterografts ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Poly(ADP-ribose) Polymerases - genetics ; Poly(ADP-ribose) Polymerases - metabolism ; Preoperative Care - methods ; Proteasome Endopeptidase Complex - genetics ; Proteasome Endopeptidase Complex - metabolism ; Radiation Tolerance - genetics ; Real-Time Polymerase Chain Reaction ; Rectal Neoplasms - genetics ; Rectal Neoplasms - pathology ; Rectal Neoplasms - radiotherapy ; Rectal Neoplasms - surgery ; Sequence Analysis, RNA - methods ; Tumor Stem Cell Assay ; Up-Regulation</subject><ispartof>International journal of radiation oncology, biology, physics, 2017-08, Vol.98 (5), p.1164-1173</ispartof><rights>2017</rights><rights>Copyright © 2017. Published by Elsevier Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c362t-35415d7b43540f05477335ba272e895bb56c8e13a1949547c64aaee52e47e2da3</citedby><cites>FETCH-LOGICAL-c362t-35415d7b43540f05477335ba272e895bb56c8e13a1949547c64aaee52e47e2da3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0360301617307095$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27903,27904,65309</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28721901$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ha, Ye Jin</creatorcontrib><creatorcontrib>Tak, Ka Hee</creatorcontrib><creatorcontrib>Kim, Chan Wook</creatorcontrib><creatorcontrib>Roh, Seon Ae</creatorcontrib><creatorcontrib>Choi, Eun Kyung</creatorcontrib><creatorcontrib>Cho, Dong Hyung</creatorcontrib><creatorcontrib>Kim, Jeong Hwan</creatorcontrib><creatorcontrib>Kim, Seon Kyu</creatorcontrib><creatorcontrib>Kim, Seon Young</creatorcontrib><creatorcontrib>Kim, Yong Sung</creatorcontrib><creatorcontrib>Kim, Jin Cheon</creatorcontrib><title>PSMB8 as a Candidate Marker of Responsiveness to Preoperative Radiation Therapy in Rectal Cancer Patients</title><title>International journal of radiation oncology, biology, physics</title><addtitle>Int J Radiat Oncol Biol Phys</addtitle><description>The ability to predict individual responsiveness to cancer therapy is urgently needed. This is particularly true for patients with locally advanced rectal cancer (LARC) because a large proportion are resistant to preoperative chemoradiation therapy (CRT). In this study, we sought to identify markers that could predict response by comparing the gene expression profiles of the tumors of patients who received preoperative CRT.
The basal gene expression profiles of tumors from 22 LARC patients who were responders (n=9) and nonresponders (n=13) to preoperative CRT were analyzed using RNA sequencing (RNA-Seq). To validate the RNA-Seq findings, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was performed on tumor samples from an additional 40 LARC patients (n=20 responders; n=20 nonresponders). Candidate genes were stably overexpressed or knocked down in colorectal cancer (CRC) cell lines, and the effect on response to radiation was tested in vitro and also in vivo in a mouse xenograft model.
Eight differentially expressed (>16-fold) genes (B3GALT4, HSPA1B, KRBOX1, PPBP, PPP1R18, PSMB8, SLC39A7, and TAP2) associated with the preoperative CRT response were identified (P<.0005). Among these genes, real-time RT-PCR showed that PSMB8 and SLC39A7 were upregulated in the responsive group of the additional 40 LARC patients. In CRC cell lines, PSMB8 overexpression significantly reduced colony formation and increased the apoptosis-inducing molecules cleaved caspase-3 and cleaved PARP after 6-Gy irradiation. PSMB8 knockdown increased colony formation and decreased caspase-3 activation and cleaved PARP levels after irradiation. SLC39A7 overexpression had no significant effects on irradiated CSC cells. After irradiation of the xenografted mice, tumors that arose from CRC cell line HCT116 overexpressing PSMB8 grew more slowly than did those from HCT116 with vector alone.
These results suggest that PSMB8 is a predictive marker of preoperative radiosensitivity in LARC patients. Clinical validation in a larger cohort is now required.</description><subject>Animals</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Caspase 3 - genetics</subject><subject>Caspase 3 - metabolism</subject><subject>Cation Transport Proteins - genetics</subject><subject>Cation Transport Proteins - metabolism</subject><subject>Cell Death</subject><subject>Cell Line, Tumor</subject><subject>Gene Expression Profiling - methods</subject><subject>Gene Knockdown Techniques</subject><subject>Gene Silencing</subject><subject>Genetic Markers</subject><subject>Heterografts</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Poly(ADP-ribose) Polymerases - genetics</subject><subject>Poly(ADP-ribose) Polymerases - metabolism</subject><subject>Preoperative Care - methods</subject><subject>Proteasome Endopeptidase Complex - genetics</subject><subject>Proteasome Endopeptidase Complex - metabolism</subject><subject>Radiation Tolerance - genetics</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Rectal Neoplasms - genetics</subject><subject>Rectal Neoplasms - pathology</subject><subject>Rectal Neoplasms - radiotherapy</subject><subject>Rectal Neoplasms - surgery</subject><subject>Sequence Analysis, RNA - methods</subject><subject>Tumor Stem Cell Assay</subject><subject>Up-Regulation</subject><issn>0360-3016</issn><issn>1879-355X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1rGzEQhkVpaZyk_6AEHXvxZvSxq91LoTH5goQax4XehFY7JnLt1UZaG_LvM8Zpjz1pmHnfd0YPY18FFAJEdbkuwjrFdigkCFOAKkCqD2wiatNMVVn-_sgmoCqYKhKfsNOc1wAghNGf2YmsjRQNiAkL86fHq5q7zB2fub4LnRuRP7r0BxOPK77APMQ-hz32mDMfI58njAMmN1KPL1wXqIo9Xz5Tb3jloSePH93mEOcpZE5z7Md8zj6t3Cbjl_f3jP26uV7O7qYPP2_vZz8epl5VcqTTtSg702oqYAWlNkapsnXSSKybsm3LytcolBONbmjqK-0cYilRG5SdU2fs2zF3SPFlh3m025A9bjaux7jLVjQSVKPBaJLqo9SnmHPClR1S2Lr0agXYA2S7tkfI9gDZgrIEmWwX7xt27Ra7f6a_VEnw_ShA-uc-YLLZEwOPXUjExnYx_H_DG8QTjsU</recordid><startdate>20170801</startdate><enddate>20170801</enddate><creator>Ha, Ye Jin</creator><creator>Tak, Ka Hee</creator><creator>Kim, Chan Wook</creator><creator>Roh, Seon Ae</creator><creator>Choi, Eun Kyung</creator><creator>Cho, Dong Hyung</creator><creator>Kim, Jeong Hwan</creator><creator>Kim, Seon Kyu</creator><creator>Kim, Seon Young</creator><creator>Kim, Yong Sung</creator><creator>Kim, Jin Cheon</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20170801</creationdate><title>PSMB8 as a Candidate Marker of Responsiveness to Preoperative Radiation Therapy in Rectal Cancer Patients</title><author>Ha, Ye Jin ; Tak, Ka Hee ; Kim, Chan Wook ; Roh, Seon Ae ; Choi, Eun Kyung ; Cho, Dong Hyung ; Kim, Jeong Hwan ; Kim, Seon Kyu ; Kim, Seon Young ; Kim, Yong Sung ; Kim, Jin Cheon</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c362t-35415d7b43540f05477335ba272e895bb56c8e13a1949547c64aaee52e47e2da3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>Caspase 3 - genetics</topic><topic>Caspase 3 - metabolism</topic><topic>Cation Transport Proteins - genetics</topic><topic>Cation Transport Proteins - metabolism</topic><topic>Cell Death</topic><topic>Cell Line, Tumor</topic><topic>Gene Expression Profiling - methods</topic><topic>Gene Knockdown Techniques</topic><topic>Gene Silencing</topic><topic>Genetic Markers</topic><topic>Heterografts</topic><topic>Humans</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Nude</topic><topic>Poly(ADP-ribose) Polymerases - genetics</topic><topic>Poly(ADP-ribose) Polymerases - metabolism</topic><topic>Preoperative Care - methods</topic><topic>Proteasome Endopeptidase Complex - genetics</topic><topic>Proteasome Endopeptidase Complex - metabolism</topic><topic>Radiation Tolerance - genetics</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>Rectal Neoplasms - genetics</topic><topic>Rectal Neoplasms - pathology</topic><topic>Rectal Neoplasms - radiotherapy</topic><topic>Rectal Neoplasms - surgery</topic><topic>Sequence Analysis, RNA - methods</topic><topic>Tumor Stem Cell Assay</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ha, Ye Jin</creatorcontrib><creatorcontrib>Tak, Ka Hee</creatorcontrib><creatorcontrib>Kim, Chan Wook</creatorcontrib><creatorcontrib>Roh, Seon Ae</creatorcontrib><creatorcontrib>Choi, Eun Kyung</creatorcontrib><creatorcontrib>Cho, Dong Hyung</creatorcontrib><creatorcontrib>Kim, Jeong Hwan</creatorcontrib><creatorcontrib>Kim, Seon Kyu</creatorcontrib><creatorcontrib>Kim, Seon Young</creatorcontrib><creatorcontrib>Kim, Yong Sung</creatorcontrib><creatorcontrib>Kim, Jin Cheon</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>International journal of radiation oncology, biology, physics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ha, Ye Jin</au><au>Tak, Ka Hee</au><au>Kim, Chan Wook</au><au>Roh, Seon Ae</au><au>Choi, Eun Kyung</au><au>Cho, Dong Hyung</au><au>Kim, Jeong Hwan</au><au>Kim, Seon Kyu</au><au>Kim, Seon Young</au><au>Kim, Yong Sung</au><au>Kim, Jin Cheon</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PSMB8 as a Candidate Marker of Responsiveness to Preoperative Radiation Therapy in Rectal Cancer Patients</atitle><jtitle>International journal of radiation oncology, biology, physics</jtitle><addtitle>Int J Radiat Oncol Biol Phys</addtitle><date>2017-08-01</date><risdate>2017</risdate><volume>98</volume><issue>5</issue><spage>1164</spage><epage>1173</epage><pages>1164-1173</pages><issn>0360-3016</issn><eissn>1879-355X</eissn><abstract>The ability to predict individual responsiveness to cancer therapy is urgently needed. This is particularly true for patients with locally advanced rectal cancer (LARC) because a large proportion are resistant to preoperative chemoradiation therapy (CRT). In this study, we sought to identify markers that could predict response by comparing the gene expression profiles of the tumors of patients who received preoperative CRT.
The basal gene expression profiles of tumors from 22 LARC patients who were responders (n=9) and nonresponders (n=13) to preoperative CRT were analyzed using RNA sequencing (RNA-Seq). To validate the RNA-Seq findings, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was performed on tumor samples from an additional 40 LARC patients (n=20 responders; n=20 nonresponders). Candidate genes were stably overexpressed or knocked down in colorectal cancer (CRC) cell lines, and the effect on response to radiation was tested in vitro and also in vivo in a mouse xenograft model.
Eight differentially expressed (>16-fold) genes (B3GALT4, HSPA1B, KRBOX1, PPBP, PPP1R18, PSMB8, SLC39A7, and TAP2) associated with the preoperative CRT response were identified (P<.0005). Among these genes, real-time RT-PCR showed that PSMB8 and SLC39A7 were upregulated in the responsive group of the additional 40 LARC patients. In CRC cell lines, PSMB8 overexpression significantly reduced colony formation and increased the apoptosis-inducing molecules cleaved caspase-3 and cleaved PARP after 6-Gy irradiation. PSMB8 knockdown increased colony formation and decreased caspase-3 activation and cleaved PARP levels after irradiation. SLC39A7 overexpression had no significant effects on irradiated CSC cells. After irradiation of the xenografted mice, tumors that arose from CRC cell line HCT116 overexpressing PSMB8 grew more slowly than did those from HCT116 with vector alone.
These results suggest that PSMB8 is a predictive marker of preoperative radiosensitivity in LARC patients. Clinical validation in a larger cohort is now required.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>28721901</pmid><doi>10.1016/j.ijrobp.2017.03.023</doi><tpages>10</tpages></addata></record> |
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| subjects | Animals Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism Caspase 3 - genetics Caspase 3 - metabolism Cation Transport Proteins - genetics Cation Transport Proteins - metabolism Cell Death Cell Line, Tumor Gene Expression Profiling - methods Gene Knockdown Techniques Gene Silencing Genetic Markers Heterografts Humans Male Mice Mice, Inbred BALB C Mice, Nude Poly(ADP-ribose) Polymerases - genetics Poly(ADP-ribose) Polymerases - metabolism Preoperative Care - methods Proteasome Endopeptidase Complex - genetics Proteasome Endopeptidase Complex - metabolism Radiation Tolerance - genetics Real-Time Polymerase Chain Reaction Rectal Neoplasms - genetics Rectal Neoplasms - pathology Rectal Neoplasms - radiotherapy Rectal Neoplasms - surgery Sequence Analysis, RNA - methods Tumor Stem Cell Assay Up-Regulation |
| title | PSMB8 as a Candidate Marker of Responsiveness to Preoperative Radiation Therapy in Rectal Cancer Patients |
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