Combined evaluation of hexokinase 2 and phosphorylated pyruvate dehydrogenase‐E1α in invasive front lesions of colorectal tumors predicts cancer metabolism and patient prognosis
Although numerous studies have shown the significance of cancer‐specific aerobic glycolysis, how glycolysis contributes to tumor invasion, a critical phenomenon in metastasis, remains unclear. With regard to colorectal cancer (CRC), we studied two critical gate enzymes, hexokinase 2 (HK2), which is...
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| Veröffentlicht in: | Cancer science 2014-09, Vol.105 (9), p.1100-1108 |
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| creator | Hamabe, Atsushi Yamamoto, Hirofumi Konno, Masamitsu Uemura, Mamoru Nishimura, Junichi Hata, Taishi Takemasa, Ichiro Mizushima, Tsunekazu Nishida, Naohiro Kawamoto, Koichi Koseki, Jun Doki, Yuichiro Mori, Masaki Ishii, Hideshi |
| description | Although numerous studies have shown the significance of cancer‐specific aerobic glycolysis, how glycolysis contributes to tumor invasion, a critical phenomenon in metastasis, remains unclear. With regard to colorectal cancer (CRC), we studied two critical gate enzymes, hexokinase 2 (HK2), which is involved in glycolysis, and phosphorylated pyruvate dehydrogenase‐E1α (p‐PDH), which is involved in oxidative phosphorylation (OxPhos). Immunohistochemical analyses using anti‐HK2 and p‐PDH antibodies were performed on surgically resected CRC samples (n = 104), and the expression in invasive front lesions of tumors was assessed. Positive HK2 expression correlated with extensive tumor diameter (P = 0.0460), advanced tumor depth (P = 0.0395), and presence of lymph node metastasis (P = 0.0409). Expression of p‐PDH tended to be higher in right‐sided CRCs than in left‐sided CRCs (P = 0.0883). In survival analysis, the combined evaluation of positive HK2 and negative p‐PDH was associated with reduced recurrence‐free survival (RFS) (P = 0.0169 in all stages and P = 0.0238 in Stage II and III patients, respectively). This evaluation could predict RFS more precisely than the independent evaluation. The present study indicated that high HK2 expression combined with low p‐PDH expression in the invasive front lesions of CRC tumors is predictive of tumor aggressiveness and survival of CRC cases.
The correlation between aerobic glycolysis and colorectal cancer invasion remains unclear. In our study, combined evaluation of hexokinase 2 and phosphorylated pyruvate dehydrogenase‐E1α in invasive front lesions of colorectal tumors could predict cancer metabolism and patient prognosis. |
| doi_str_mv | 10.1111/cas.12487 |
| format | Article |
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The correlation between aerobic glycolysis and colorectal cancer invasion remains unclear. In our study, combined evaluation of hexokinase 2 and phosphorylated pyruvate dehydrogenase‐E1α in invasive front lesions of colorectal tumors could predict cancer metabolism and patient prognosis.</description><identifier>ISSN: 1347-9032</identifier><identifier>EISSN: 1349-7006</identifier><identifier>DOI: 10.1111/cas.12487</identifier><identifier>PMID: 25060325</identifier><language>eng</language><publisher>England: John Wiley & Sons, Inc</publisher><subject>Adenocarcinoma - enzymology ; Adenocarcinoma - mortality ; Adenocarcinoma - pathology ; Aged ; Cancer ; Cell Line, Tumor ; Chemotherapy ; Colorectal cancer ; Colorectal carcinoma ; Colorectal Neoplasms - enzymology ; Colorectal Neoplasms - mortality ; Colorectal Neoplasms - pathology ; Dehydrogenases ; Disease-Free Survival ; Female ; Glycolysis ; Hexokinase ; Hexokinase - metabolism ; Humans ; Immunoglobulins ; Intestinal Mucosa - enzymology ; Intestinal Mucosa - pathology ; invasion ; Invasiveness ; Kaplan-Meier Estimate ; Kinases ; Laboratories ; Lymph nodes ; Male ; Medical prognosis ; Medical research ; Melanoma ; Metabolism ; Metabolites ; Metastases ; Metastasis ; Middle Aged ; Mitochondria ; Multivariate Analysis ; Neoplasm Invasiveness ; Neoplasm Recurrence, Local - enzymology ; Original ; Oxidative phosphorylation ; Phosphoproteins - metabolism ; Phosphorylation ; Protein Processing, Post-Translational ; pyruvate dehydrogenase ; Pyruvate Dehydrogenase (Lipoamide) - metabolism ; Pyruvic acid ; Studies ; Survival ; Tumors</subject><ispartof>Cancer science, 2014-09, Vol.105 (9), p.1100-1108</ispartof><rights>2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.</rights><rights>2014. This work is published under http://creativecommons.org/licenses/by-nc-nd/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association. 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4677-fe46bc87533e0872e2afb85c1894a6cc809827035f0ab7b54bbd2b1a0728afeb3</citedby><cites>FETCH-LOGICAL-c4677-fe46bc87533e0872e2afb85c1894a6cc809827035f0ab7b54bbd2b1a0728afeb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462394/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462394/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,1416,11561,27923,27924,45573,45574,46051,46475,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25060325$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hamabe, Atsushi</creatorcontrib><creatorcontrib>Yamamoto, Hirofumi</creatorcontrib><creatorcontrib>Konno, Masamitsu</creatorcontrib><creatorcontrib>Uemura, Mamoru</creatorcontrib><creatorcontrib>Nishimura, Junichi</creatorcontrib><creatorcontrib>Hata, Taishi</creatorcontrib><creatorcontrib>Takemasa, Ichiro</creatorcontrib><creatorcontrib>Mizushima, Tsunekazu</creatorcontrib><creatorcontrib>Nishida, Naohiro</creatorcontrib><creatorcontrib>Kawamoto, Koichi</creatorcontrib><creatorcontrib>Koseki, Jun</creatorcontrib><creatorcontrib>Doki, Yuichiro</creatorcontrib><creatorcontrib>Mori, Masaki</creatorcontrib><creatorcontrib>Ishii, Hideshi</creatorcontrib><title>Combined evaluation of hexokinase 2 and phosphorylated pyruvate dehydrogenase‐E1α in invasive front lesions of colorectal tumors predicts cancer metabolism and patient prognosis</title><title>Cancer science</title><addtitle>Cancer Sci</addtitle><description>Although numerous studies have shown the significance of cancer‐specific aerobic glycolysis, how glycolysis contributes to tumor invasion, a critical phenomenon in metastasis, remains unclear. With regard to colorectal cancer (CRC), we studied two critical gate enzymes, hexokinase 2 (HK2), which is involved in glycolysis, and phosphorylated pyruvate dehydrogenase‐E1α (p‐PDH), which is involved in oxidative phosphorylation (OxPhos). Immunohistochemical analyses using anti‐HK2 and p‐PDH antibodies were performed on surgically resected CRC samples (n = 104), and the expression in invasive front lesions of tumors was assessed. Positive HK2 expression correlated with extensive tumor diameter (P = 0.0460), advanced tumor depth (P = 0.0395), and presence of lymph node metastasis (P = 0.0409). Expression of p‐PDH tended to be higher in right‐sided CRCs than in left‐sided CRCs (P = 0.0883). In survival analysis, the combined evaluation of positive HK2 and negative p‐PDH was associated with reduced recurrence‐free survival (RFS) (P = 0.0169 in all stages and P = 0.0238 in Stage II and III patients, respectively). This evaluation could predict RFS more precisely than the independent evaluation. The present study indicated that high HK2 expression combined with low p‐PDH expression in the invasive front lesions of CRC tumors is predictive of tumor aggressiveness and survival of CRC cases.
The correlation between aerobic glycolysis and colorectal cancer invasion remains unclear. In our study, combined evaluation of hexokinase 2 and phosphorylated pyruvate dehydrogenase‐E1α in invasive front lesions of colorectal tumors could predict cancer metabolism and patient prognosis.</description><subject>Adenocarcinoma - enzymology</subject><subject>Adenocarcinoma - mortality</subject><subject>Adenocarcinoma - pathology</subject><subject>Aged</subject><subject>Cancer</subject><subject>Cell Line, Tumor</subject><subject>Chemotherapy</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Colorectal Neoplasms - enzymology</subject><subject>Colorectal Neoplasms - mortality</subject><subject>Colorectal Neoplasms - pathology</subject><subject>Dehydrogenases</subject><subject>Disease-Free Survival</subject><subject>Female</subject><subject>Glycolysis</subject><subject>Hexokinase</subject><subject>Hexokinase - metabolism</subject><subject>Humans</subject><subject>Immunoglobulins</subject><subject>Intestinal Mucosa - enzymology</subject><subject>Intestinal Mucosa - pathology</subject><subject>invasion</subject><subject>Invasiveness</subject><subject>Kaplan-Meier Estimate</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>Lymph nodes</subject><subject>Male</subject><subject>Medical prognosis</subject><subject>Medical research</subject><subject>Melanoma</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Middle Aged</subject><subject>Mitochondria</subject><subject>Multivariate Analysis</subject><subject>Neoplasm Invasiveness</subject><subject>Neoplasm Recurrence, Local - enzymology</subject><subject>Original</subject><subject>Oxidative phosphorylation</subject><subject>Phosphoproteins - metabolism</subject><subject>Phosphorylation</subject><subject>Protein Processing, Post-Translational</subject><subject>pyruvate dehydrogenase</subject><subject>Pyruvate Dehydrogenase (Lipoamide) - metabolism</subject><subject>Pyruvic acid</subject><subject>Studies</subject><subject>Survival</subject><subject>Tumors</subject><issn>1347-9032</issn><issn>1349-7006</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1ks2O1SAUgBujccbRhS9gSNzoojNAaaEbk8nN-JNM4kJdE6CncxkpVGg73p2P4KuY-Bw-hE8idzpO1EQC4QS-fOcQTlE8JviY5HFiVDomlAl-pzgkFWtLjnFz9zrmZYsrelA8SOkS46phLbtfHNAaN_m4Piy-b8KgrYcOwaLcrCYbPAo92sLn8NF6lQBRpHyHxm1IecWdU1Omx12clxyhDra7LoYL2LM_v3w9Iz--IevzXFSyC6A-Bj8hBymb015tggsRzKQcmuYhxITGCJ01U0JGeQMRDTApHZxNw5o6VwXZMeY0PiSbHhb3euUSPLrZj4oPL8_eb16X529fvdmcnpeGNZyXPbBGG8HrqgIsOAWqei1qQ0TLVGOMwK2gHFd1j5XmumZad1QThTkVqgddHRUvVu846wE6k4uIyskx2kHFnQzKyr9vvN3Ki7BIxhpatSwLnt0IYvg0Q5rkYJMB55SHMCdJ6qYhWAhaZ_TpP-hlmKPPz5OUtpjWFAuSqecrZWJIKUJ_WwzBct8LMveCvO6FzD75s_pb8vfnZ-BkBa6sg93_TXJz-m5V_gJm5MWn</recordid><startdate>201409</startdate><enddate>201409</enddate><creator>Hamabe, Atsushi</creator><creator>Yamamoto, Hirofumi</creator><creator>Konno, Masamitsu</creator><creator>Uemura, Mamoru</creator><creator>Nishimura, Junichi</creator><creator>Hata, Taishi</creator><creator>Takemasa, Ichiro</creator><creator>Mizushima, Tsunekazu</creator><creator>Nishida, Naohiro</creator><creator>Kawamoto, Koichi</creator><creator>Koseki, Jun</creator><creator>Doki, Yuichiro</creator><creator>Mori, Masaki</creator><creator>Ishii, Hideshi</creator><general>John Wiley & Sons, Inc</general><general>BlackWell Publishing Ltd</general><scope>24P</scope><scope>WIN</scope><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>8FE</scope><scope>8FH</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201409</creationdate><title>Combined evaluation of hexokinase 2 and phosphorylated pyruvate dehydrogenase‐E1α in invasive front lesions of colorectal tumors predicts cancer metabolism and patient prognosis</title><author>Hamabe, Atsushi ; Yamamoto, Hirofumi ; Konno, Masamitsu ; Uemura, Mamoru ; Nishimura, Junichi ; Hata, Taishi ; Takemasa, Ichiro ; Mizushima, Tsunekazu ; Nishida, Naohiro ; Kawamoto, Koichi ; Koseki, Jun ; Doki, Yuichiro ; Mori, Masaki ; Ishii, Hideshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4677-fe46bc87533e0872e2afb85c1894a6cc809827035f0ab7b54bbd2b1a0728afeb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adenocarcinoma - enzymology</topic><topic>Adenocarcinoma - mortality</topic><topic>Adenocarcinoma - pathology</topic><topic>Aged</topic><topic>Cancer</topic><topic>Cell Line, Tumor</topic><topic>Chemotherapy</topic><topic>Colorectal cancer</topic><topic>Colorectal carcinoma</topic><topic>Colorectal Neoplasms - enzymology</topic><topic>Colorectal Neoplasms - mortality</topic><topic>Colorectal Neoplasms - pathology</topic><topic>Dehydrogenases</topic><topic>Disease-Free Survival</topic><topic>Female</topic><topic>Glycolysis</topic><topic>Hexokinase</topic><topic>Hexokinase - metabolism</topic><topic>Humans</topic><topic>Immunoglobulins</topic><topic>Intestinal Mucosa - enzymology</topic><topic>Intestinal Mucosa - pathology</topic><topic>invasion</topic><topic>Invasiveness</topic><topic>Kaplan-Meier Estimate</topic><topic>Kinases</topic><topic>Laboratories</topic><topic>Lymph nodes</topic><topic>Male</topic><topic>Medical prognosis</topic><topic>Medical research</topic><topic>Melanoma</topic><topic>Metabolism</topic><topic>Metabolites</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Middle Aged</topic><topic>Mitochondria</topic><topic>Multivariate Analysis</topic><topic>Neoplasm Invasiveness</topic><topic>Neoplasm Recurrence, Local - enzymology</topic><topic>Original</topic><topic>Oxidative phosphorylation</topic><topic>Phosphoproteins - metabolism</topic><topic>Phosphorylation</topic><topic>Protein Processing, Post-Translational</topic><topic>pyruvate dehydrogenase</topic><topic>Pyruvate Dehydrogenase (Lipoamide) - metabolism</topic><topic>Pyruvic acid</topic><topic>Studies</topic><topic>Survival</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hamabe, Atsushi</creatorcontrib><creatorcontrib>Yamamoto, Hirofumi</creatorcontrib><creatorcontrib>Konno, Masamitsu</creatorcontrib><creatorcontrib>Uemura, Mamoru</creatorcontrib><creatorcontrib>Nishimura, Junichi</creatorcontrib><creatorcontrib>Hata, Taishi</creatorcontrib><creatorcontrib>Takemasa, Ichiro</creatorcontrib><creatorcontrib>Mizushima, Tsunekazu</creatorcontrib><creatorcontrib>Nishida, Naohiro</creatorcontrib><creatorcontrib>Kawamoto, Koichi</creatorcontrib><creatorcontrib>Koseki, Jun</creatorcontrib><creatorcontrib>Doki, Yuichiro</creatorcontrib><creatorcontrib>Mori, Masaki</creatorcontrib><creatorcontrib>Ishii, Hideshi</creatorcontrib><collection>Wiley-Blackwell Open Access Titles</collection><collection>Wiley Free Content</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</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>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hamabe, Atsushi</au><au>Yamamoto, Hirofumi</au><au>Konno, Masamitsu</au><au>Uemura, Mamoru</au><au>Nishimura, Junichi</au><au>Hata, Taishi</au><au>Takemasa, Ichiro</au><au>Mizushima, Tsunekazu</au><au>Nishida, Naohiro</au><au>Kawamoto, Koichi</au><au>Koseki, Jun</au><au>Doki, Yuichiro</au><au>Mori, Masaki</au><au>Ishii, Hideshi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Combined evaluation of hexokinase 2 and phosphorylated pyruvate dehydrogenase‐E1α in invasive front lesions of colorectal tumors predicts cancer metabolism and patient prognosis</atitle><jtitle>Cancer science</jtitle><addtitle>Cancer Sci</addtitle><date>2014-09</date><risdate>2014</risdate><volume>105</volume><issue>9</issue><spage>1100</spage><epage>1108</epage><pages>1100-1108</pages><issn>1347-9032</issn><eissn>1349-7006</eissn><abstract>Although numerous studies have shown the significance of cancer‐specific aerobic glycolysis, how glycolysis contributes to tumor invasion, a critical phenomenon in metastasis, remains unclear. With regard to colorectal cancer (CRC), we studied two critical gate enzymes, hexokinase 2 (HK2), which is involved in glycolysis, and phosphorylated pyruvate dehydrogenase‐E1α (p‐PDH), which is involved in oxidative phosphorylation (OxPhos). Immunohistochemical analyses using anti‐HK2 and p‐PDH antibodies were performed on surgically resected CRC samples (n = 104), and the expression in invasive front lesions of tumors was assessed. Positive HK2 expression correlated with extensive tumor diameter (P = 0.0460), advanced tumor depth (P = 0.0395), and presence of lymph node metastasis (P = 0.0409). Expression of p‐PDH tended to be higher in right‐sided CRCs than in left‐sided CRCs (P = 0.0883). In survival analysis, the combined evaluation of positive HK2 and negative p‐PDH was associated with reduced recurrence‐free survival (RFS) (P = 0.0169 in all stages and P = 0.0238 in Stage II and III patients, respectively). This evaluation could predict RFS more precisely than the independent evaluation. The present study indicated that high HK2 expression combined with low p‐PDH expression in the invasive front lesions of CRC tumors is predictive of tumor aggressiveness and survival of CRC cases.
The correlation between aerobic glycolysis and colorectal cancer invasion remains unclear. In our study, combined evaluation of hexokinase 2 and phosphorylated pyruvate dehydrogenase‐E1α in invasive front lesions of colorectal tumors could predict cancer metabolism and patient prognosis.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>25060325</pmid><doi>10.1111/cas.12487</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Cancer science, 2014-09, Vol.105 (9), p.1100-1108 |
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| subjects | Adenocarcinoma - enzymology Adenocarcinoma - mortality Adenocarcinoma - pathology Aged Cancer Cell Line, Tumor Chemotherapy Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - enzymology Colorectal Neoplasms - mortality Colorectal Neoplasms - pathology Dehydrogenases Disease-Free Survival Female Glycolysis Hexokinase Hexokinase - metabolism Humans Immunoglobulins Intestinal Mucosa - enzymology Intestinal Mucosa - pathology invasion Invasiveness Kaplan-Meier Estimate Kinases Laboratories Lymph nodes Male Medical prognosis Medical research Melanoma Metabolism Metabolites Metastases Metastasis Middle Aged Mitochondria Multivariate Analysis Neoplasm Invasiveness Neoplasm Recurrence, Local - enzymology Original Oxidative phosphorylation Phosphoproteins - metabolism Phosphorylation Protein Processing, Post-Translational pyruvate dehydrogenase Pyruvate Dehydrogenase (Lipoamide) - metabolism Pyruvic acid Studies Survival Tumors |
| title | Combined evaluation of hexokinase 2 and phosphorylated pyruvate dehydrogenase‐E1α in invasive front lesions of colorectal tumors predicts cancer metabolism and patient prognosis |
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