{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T16:15:28Z","timestamp":1789748128711,"version":"4.0.1"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2011,6,10]],"date-time":"2011-06-10T00:00:00Z","timestamp":1307664000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Nature Science Foundation of China","doi-asserted-by":"crossref","award":["no. 30973500"],"award-info":[{"award-number":["no. 30973500"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background.<\/jats:title>\n                  <jats:p>Hepatocellular carcinoma (HCC) most commonly develops in patients who have a viral infection, especially in the case of hepatitis B virus (HBV), and in patients with a chronic liver disease. HCC patients with bone metastasis (BM) suffer from pain and other symptoms that significantly reduce their quality of life. Identification of patients who are at high risk for BM after undergoing potentially curative treatment for HCC remains challenging. Here, we aimed to identify HCC BM-related genes and proteins to establish prediction biomarkers.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods.<\/jats:title>\n                  <jats:p>RNA was extracted from 48 pairs of intratumoral and peritumoral formalin-fixed, paraffin-embedded tissue from HCC patients with and without BM. A cDNA-mediated annealing, selection, extension and ligation assay containing 502 cancer-related genes was used to identify novel BM-associated genes. An additional independent study with 350 HCC patients who had undergone hepatectomy was conducted to evaluate the expression of candidate genes at the protein level using immunohistochemistry on tissue microarrays (TMAs). Of the 350 patients, 273 (78.0%) were infected with HBV.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results.<\/jats:title>\n                  <jats:p>Seven intratumoral genes and 17 peritumoral genes were overexpressed in patients with BM, whereas 15 intratumoral genes and 28 peritumoral genes were underexpressed in patients with BM. We selected the following four genes for further analysis because they were differentially expressed in the cancer gene-specific microarray and were previously reported to be associated with BM: connective tissue growth factor (CTGF), matrix metalloproteinase-1 (MMP-1), transforming growth factor \u03b21 (TGF-\u03b21), and interleukin-11 (IL-11). We assessed the protein expression of these selected genes using immunohistochemistry on TMAs including 350 HCC patient specimens. We determined that expression of intratumoral CTGF, intratumoral IL-11, and peritumoral MMP-1 were independent prognostic factors for developing BM in HCC patients. Combining intratumoral CTGF and IL-11 expression was also an independent risk factor for BM development.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions.<\/jats:title>\n                  <jats:p>Sixty-seven genes were differentially expressed in HCC patients with and without BM. High intratumoral CTGF, positive IL-11, and high peritumoral MMP-1 expression were associated with BM after hepatectomy. Intratumoral CTGF expression combined with IL-11 expression may serve as a useful predictive biomarker for HCC BM.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1634\/theoncologist.2010-0358","type":"journal-article","created":{"date-parts":[[2011,6,11]],"date-time":"2011-06-11T01:04:45Z","timestamp":1307754285000},"page":"1028-1039","source":"Crossref","is-referenced-by-count":42,"title":["Potential Prognostic Biomarkers for Bone Metastasis from Hepatocellular Carcinoma"],"prefix":"10.1093","volume":"16","author":[{"given":"Zuo-Lin","family":"Xiang","sequence":"first","affiliation":[{"name":"a Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao-Chong","family":"Zeng","sequence":"additional","affiliation":[{"name":"a Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao-You","family":"Tang","sequence":"additional","affiliation":[{"name":"b Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Fan","sequence":"additional","affiliation":[{"name":"b Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"He","sequence":"additional","affiliation":[{"name":"a Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-Ying","family":"Zeng","sequence":"additional","affiliation":[{"name":"c Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Dong","family":"Zhu","sequence":"additional","affiliation":[{"name":"b Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2011,6,10]]},"reference":[{"key":"2021122310064252200_B1","doi-asserted-by":"crossref","first-page":"74","DOI":"10.3322\/canjclin.55.2.74","article-title":"Global cancer statistics, 2002","volume":"55","author":"Parkin","year":"2005","journal-title":"CA Cancer J Clin"},{"key":"2021122310064252200_B2","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/S0140-6736(05)78179-4","article-title":"Trends in primary liver cancer","volume":"351","author":"Deuffic","year":"1998","journal-title":"Lancet"},{"key":"2021122310064252200_B3","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1056\/NEJM199903113401001","article-title":"Rising incidence of hepatocellular carcinoma in the United States","volume":"340","author":"El Serag","year":"1999","journal-title":"N Engl J Med"},{"key":"2021122310064252200_B4","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1111\/j.1440-1746.2005.03919.x","article-title":"Clinical features of hepatocellular carcinoma with extrahepatic metastases","volume":"20","author":"Natsuizaka","year":"2005","journal-title":"J Gastroenterol Hepatol"},{"key":"2021122310064252200_B5","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1056\/NEJMra030831","article-title":"Mechanisms of bone metastasis","volume":"350","author":"Roodman","year":"2004","journal-title":"N Engl J Med"},{"key":"2021122310064252200_B6","doi-asserted-by":"crossref","first-page":"2710","DOI":"10.1002\/cncr.24300","article-title":"Clinical features and prognostic factors in patients with bone metastases from hepatocellular carcinoma receiving external beam radiotherapy","volume":"115","author":"He","year":"2009","journal-title":"Cancer"},{"key":"2021122310064252200_B7","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1038\/nbt0904-1071","article-title":"Coming soon: A global grid for cancer research","volume":"22","author":"Bouchie","year":"2004","journal-title":"Nat Biotechnol"},{"key":"2021122310064252200_B8","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.1056\/NEJMp048059","article-title":"Translating cancer genomics into clinical oncology","volume":"350","author":"Ramaswamy","year":"2004","journal-title":"N Engl J Med"},{"key":"2021122310064252200_B9","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1016\/S0002-9440(10)63435-9","article-title":"Quantitative gene expression profiling in formalin-fixed, paraffin-embedded tissues using universal bead arrays","volume":"165","author":"Bibikova","year":"2004","journal-title":"Am J Pathol"},{"key":"2021122310064252200_B10","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1101\/gr.2167504","article-title":"A versatile assay for high-throughput gene expression profiling on universal array matrices","volume":"14","author":"Fan","year":"2004","journal-title":"Genome Res"},{"key":"2021122310064252200_B11","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1056\/NEJMoa0804525","article-title":"Gene expression in fixed tissues and outcome in hepatocellular carcinoma","volume":"359","author":"Hoshida","year":"2008","journal-title":"N Engl J Med"},{"key":"2021122310064252200_B12","doi-asserted-by":"crossref","first-page":"e8162","DOI":"10.1371\/journal.pone.0008162","article-title":"Whole-genome gene expression profiling of formalin-fixed, paraffin-embedded tissue samples","volume":"4","author":"April","year":"2009","journal-title":"PLoS One"},{"key":"2021122310064252200_B13","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1038\/labinvest.2008.11","article-title":"Quantitative expression profiling of highly degraded RNA from formalin-fixed, paraffin-embedded breast tumor biopsies by oligonucleotide microarrays","volume":"88","author":"Ravo","year":"2008","journal-title":"Lab Invest"},{"key":"2021122310064252200_B14","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1200\/JCO.2002.07.089","article-title":"Tumor microvessel density as a predictor of recurrence after resection of hepatocellular carcinoma: A prospective study","volume":"20","author":"Poon","year":"2002","journal-title":"J Clin Oncol"},{"key":"2021122310064252200_B15","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1097\/PPO.0b013e3181c6aa6b","article-title":"Increased expression of vascular endothelial growth factor-C and nuclear CXCR4 in hepatocellular carcinoma is correlated with lymph node metastasis and poor outcome","volume":"15","author":"Xiang","year":"2009","journal-title":"Cancer J"},{"key":"2021122310064252200_B16","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1186\/1471-2407-9-176","article-title":"Chemokine receptor CXCR4 expression in hepatocellular carcinoma patients increases the risk of bone metastases and poor survival","volume":"9","author":"Xiang","year":"2009","journal-title":"BMC Cancer"},{"key":"2021122310064252200_B17","doi-asserted-by":"crossref","first-page":"2740","DOI":"10.1002\/cncr.23488","article-title":"Two pathologic types of hepatocellular carcinoma with lymph node metastasis with distinct prognosis on the basis of CK19 expression in tumor","volume":"112","author":"Zhuang","year":"2008","journal-title":"Cancer"},{"key":"2021122310064252200_B18","doi-asserted-by":"crossref","first-page":"2586","DOI":"10.1200\/JCO.2006.09.4565","article-title":"Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection","volume":"25","author":"Gao","year":"2007","journal-title":"J Clin Oncol"},{"key":"2021122310064252200_B19","doi-asserted-by":"crossref","first-page":"2707","DOI":"10.1200\/JCO.2007.15.6521","article-title":"High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma","volume":"26","author":"Zhu","year":"2008","journal-title":"J Clin Oncol"},{"key":"2021122310064252200_B20","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1002\/cncr.22206","article-title":"P48 is a predictive marker for outcome of postoperative interferon-alpha treatment in patients with hepatitis B virus infection-related hepatocellular carcinoma","volume":"107","author":"Qian","year":"2006","journal-title":"Cancer"},{"key":"2021122310064252200_B21","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1053\/j.gastro.2004.10.007","article-title":"Connective tissue growth factor inhibits metastasis and acts as an independent prognostic marker in colorectal cancer","volume":"128","author":"Lin","year":"2005","journal-title":"Gastroenterology"},{"key":"2021122310064252200_B22","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.jss.2006.10.005","article-title":"TGF\u03b21, TGF\u03b22, and TGF\u03b23 protein expression in gastric carcinomas: Correlation with prognostics factors and patient survival","volume":"139","author":"Vagenas","year":"2007","journal-title":"J Surg Res"},{"key":"2021122310064252200_B23","doi-asserted-by":"crossref","first-page":"317","DOI":"10.3748\/wjg.v12.i2.317","article-title":"Expression of interleukin-11 and interleukin-11 receptor alpha in human colorectal adenocarcinoma: Iimmunohistochemical analyses and correlation with clinicopathological factors","volume":"12","author":"Yamazumi","year":"2006","journal-title":"World J Gastroenterol"},{"key":"2021122310064252200_B24","doi-asserted-by":"crossref","first-page":"1802","DOI":"10.1200\/JCO.1999.17.6.1802","article-title":"Expression and prognostic significance of metalloproteinases and their tissue inhibitors in patients with small-cell lung cancer","volume":"17","author":"Michael","year":"1999","journal-title":"J Clin Oncol"},{"key":"2021122310064252200_B25","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/S1535-6108(03)00132-6","article-title":"A multigenic program mediating breast cancer metastasis to bone","volume":"3","author":"Kang","year":"2003","journal-title":"Cancer Cell"},{"key":"2021122310064252200_B26","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.ccr.2005.07.013","article-title":"Metastasis gets site specific","volume":"8","author":"Horak","year":"2005","journal-title":"Cancer Cell"},{"key":"2021122310064252200_B27","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1172\/JCI22320","article-title":"Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors","volume":"115","author":"Minn","year":"2005","journal-title":"J Clin Invest"},{"key":"2021122310064252200_B28","doi-asserted-by":"crossref","first-page":"13909","DOI":"10.1073\/pnas.0506517102","article-title":"Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway","volume":"102","author":"Kang","year":"2005","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2021122310064252200_B29","doi-asserted-by":"crossref","first-page":"1742","DOI":"10.1016\/S0140-6736(07)60781-8","article-title":"Metastasis: Recent discoveries and novel treatment strategies","volume":"369","author":"Eccles","year":"2007","journal-title":"Lancet"},{"key":"2021122310064252200_B30","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1359\/jbmr.061005","article-title":"TGF-\u03b2 promotes the establishment of renal cell carcinoma bone metastasis","volume":"22","author":"Kominsky","year":"2007","journal-title":"J Bone Miner Res"},{"key":"2021122310064252200_B31","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1038\/onc.2008.454","article-title":"Transforming growth factor-\u03b21 is the predominant isoform required for breast cancer cell outgrowth in bone","volume":"28","author":"Mourskaia","year":"2009","journal-title":"Oncogene"},{"key":"2021122310064252200_B32","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/ng1060","article-title":"A molecular signature of metastasis in primary solid tumors","volume":"33","author":"Ramaswamy","year":"2003","journal-title":"Nat Genet"},{"key":"2021122310064252200_B33","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1038\/nm843","article-title":"Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning","volume":"9","author":"Ye","year":"2003","journal-title":"Nat Med"},{"key":"2021122310064252200_B34","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.ccr.2006.06.016","article-title":"Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment","volume":"10","author":"Budhu","year":"2006","journal-title":"Cancer Cell"},{"key":"2021122310064252200_B35","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1007\/s11926-002-0009-x","article-title":"Connective tissue growth factor: A new and important player in the pathogenesis of fibrosis","volume":"4","author":"Leask","year":"2002","journal-title":"Curr Rheumatol Rep"},{"key":"2021122310064252200_B36","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1002\/hep.23285","article-title":"Down-regulation of connective tissue growth factor by inhibition of transforming growth factor beta blocks the tumor-stroma cross-talk and tumor progression in hepatocellular carcinoma","volume":"51","author":"Mazzocca","year":"2010","journal-title":"Hepatology"},{"key":"2021122310064252200_B37","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1158\/0008-5472.CAN-08-0987","article-title":"The role of tumor cell-derived connective tissue growth factor (CTGF\/CCN2) in pancreatic tumor growth","volume":"69","author":"Bennewith","year":"2009","journal-title":"Cancer Res"},{"key":"2021122310064252200_B38","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1007\/s00268-001-0242-x","article-title":"Connective tissue growth factor gene expression alters tumor progression in esophageal cancer","volume":"26","author":"Koliopanos","year":"2002","journal-title":"World J Surg"},{"key":"2021122310064252200_B39","doi-asserted-by":"crossref","first-page":"2072","DOI":"10.1158\/1078-0432.CCR-0659-03","article-title":"Levels of expression of CYR61 and CTGF are prognostic for tumor progression and survival of individuals with gliomas","volume":"10","author":"Xie","year":"2004","journal-title":"Clin Cancer Res"},{"key":"2021122310064252200_B40","doi-asserted-by":"crossref","first-page":"3080","DOI":"10.1182\/blood-2006-06-031096","article-title":"Connective tissue growth factor (CTGF) expression and outcome in adult patients with acute lymphoblastic leukemia","volume":"109","author":"Sala-Torra","year":"2007","journal-title":"Blood"},{"key":"2021122310064252200_B41","doi-asserted-by":"crossref","first-page":"2631","DOI":"10.1158\/1078-0432.CCR-07-1991","article-title":"Serial analysis of gene expression identifies connective tissue growth factor expression as a prognostic biomarker in gallbladder cancer","volume":"14","author":"Alvarez","year":"2008","journal-title":"Clin Cancer Res"},{"key":"2021122310064252200_B42","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1093\/jnci\/djh059","article-title":"Connective tissue growth factor and its role in lung adenocarcinoma invasion and metastasis","volume":"96","author":"Chang","year":"2004","journal-title":"J Natl Cancer Inst"},{"key":"2021122310064252200_B43","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1172\/JCI117130","article-title":"Interleukin-11: A new cytokine critical for osteoclast development","volume":"93","author":"Girasole","year":"1994","journal-title":"J Clin Invest"},{"key":"2021122310064252200_B44","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/sj.onc.1201581","article-title":"Production of interleukin-11 in bone-derived endothelial cells and its role in the formation of osteolytic bone metastasis","volume":"16","author":"Zhang","year":"1998","journal-title":"Oncogene"},{"key":"2021122310064252200_B45","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1053\/j.gastro.2008.12.003","article-title":"The interleukin-6 family cytokine interleukin-11 regulates homeostatic epithelial cell turnover and promotes gastric tumor development","volume":"136","author":"Howlett","year":"2009","journal-title":"Gastroenterology"},{"key":"2021122310064252200_B46","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1245\/ASO.2006.05.028","article-title":"Expression of interleukin 11 and its receptor and their prognostic value in human breast cancer","volume":"13","author":"Hanavadi","year":"2006","journal-title":"Ann Surg Oncol"},{"key":"2021122310064252200_B47","first-page":"869","article-title":"Expression of interleukin (IL)-11 and IL-11 receptor in human colorectal adenocarcinoma: IL-11 up-regulation of the invasive and proliferative activity of human colorectal carcinoma cells","volume":"29","author":"Yoshizaki","year":"2006","journal-title":"Int J Oncol"},{"key":"2021122310064252200_B48","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/S0304-3835(01)00524-9","article-title":"Interleukins-6 and -11 expression in primary breast cancer and subsequent development of bone metastases","volume":"169","author":"Sotiriou","year":"2001","journal-title":"Cancer Lett"},{"key":"2021122310064252200_B49","first-page":"98","article-title":"The distribution of secondary growths in cancer of the breast.","volume":"8","author":"Paget","year":"1989","journal-title":"Cancer Metastasis Rev"}],"container-title":["The Oncologist"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1634\/theoncologist.2010-0358","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1634\/theoncologist.2010-0358","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/16\/7\/1028\/41901001\/oncolo_16_7_1028.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/16\/7\/1028\/41901001\/oncolo_16_7_1028.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,24]],"date-time":"2021-12-24T04:52:24Z","timestamp":1640321544000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/oncolo\/article\/16\/7\/1028\/6401070"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,6,10]]},"references-count":49,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2011,6,10]]},"published-print":{"date-parts":[[2011,7,1]]}},"URL":"https:\/\/doi.org\/10.1634\/theoncologist.2010-0358","relation":{},"ISSN":["1083-7159","1549-490X"],"issn-type":[{"value":"1083-7159","type":"print"},{"value":"1549-490X","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2011,7,1]]},"published":{"date-parts":[[2011,6,10]]}}}