骨桥蛋白在鼻咽癌组织中的表达及临床意义
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摘要
背景：鼻咽癌(nasopharyngeal carcinoma, NPC)是一种原发于鼻咽部的恶性肿瘤,它的病因、发生、发展及治疗等在诸方面均与其他头颈肿瘤有极大地不同。NPC在中国的南方地区比其他地区更为常见。它的发病机制是一个复杂的过程,主要涉及到遗传易感性、EB病毒感染和环境因素等,但是很多具体机制还不清楚。骨桥蛋白(osteopontin, OPN)是一种重要的多功能细胞外基质磷酸化糖蛋白。近来,研究表明OPN在多种肿瘤中都过度表达,包括肺癌、乳腺癌、结肠直肠癌、胃癌、卵巢癌、黑色素瘤和间皮瘤等。OPN通过与广泛分布在细胞表面上的受体相互作用,参与多种癌的许多生理和病理过程,主要涉及肿瘤的恶性转化、浸润、转移和发展等。甚至有人提出OPN可以作为肿瘤分子靶向治疗的一个靶点。目前,OPN在NPC组织的表达情况及其意义尚有待于阐明。
目的：研究OPN在NPC组织标本中表达情况并且探讨其在NPC中的意义；为NPC的早期诊断和临床治疗提供参考指标和理论基础。
试验设计、材料和方法：用横向调查的方法对NPC、慢性鼻咽炎组织和癌旁非癌组织进行研究。用半定量逆转录多聚酶链式反应(RT-PCR)的方法测定OPN mRNA在新鲜的冰冻组织中的相对表达,mRNA的含量用图像分析技术来定量；用免疫组织化学法(IHC)对石蜡包埋的组织切片中OPN的表达的程度、强度和定位进行评估。统计分析OPN mRNA和OPN蛋白的表达和NPC患者临床参数之间的关系。我们还用蛋白印迹法(WB)检测了12对NPC癌组织和癌旁非癌组织的配对标本中OPN蛋白的表达情况。
结果：从半定量RT-PCR的结果中我们得到OPN/GAPDH(mRNA灰度值)的均数(±标准差)在44例NPC组织中为0.80(±0.24),相比之下15例慢性炎症组织中仅为0.32(±0.18),二组之间有统计学意义(P<0.05)。IHC染色显示OPN蛋白主要定位于肿瘤细胞的细胞浆中,其阳性表达率在67例NPC组织中(88.1%%)显著高于21例慢性鼻咽炎组织中的阳性率(28.6%)(P<0.05)。对以上两个结果统计学分析显示OPN mRNA和OPN蛋白的表达均和年龄和性别无关(P>0.05),与肿瘤的T、N和临床分期有关(P<0.05)。WB结果显示OPN蛋白的表达水平在癌组织中高于相对应的癌旁非癌组织中的表达,平均OPN/β-Actin(灰度值)分别为0.83(±0.16)和0.51(±0.21),二组有显著差异(P<0.05)。
结论：我们的研究结果表明OPN mRNA和OPN蛋白在NPC组织中过度表达,推测它可能参与了NPC的恶性转化；OPN mRNA和OPN蛋白的表达和NPC的临床参数密切相关,推测它在NPC的侵袭、转移和进展中起到某种作用。
Context:Nasopharyngeal carcinoma (NPC) is a malignant tumor originating in the nasopharynx, it differs overwhelmingly from other tumors of the head and neck in its causes, occurrence, progression, and treatment. It is vastly more common in southern regions of China than elsewhere. The pathogenesis of nasopharyngeal carcinoma is a complicated process principally involving genetic predisposition, Epstein-Bar Virus infection and environmental factors etc.. However, there are many specific pathogenesis are unclear. Osteopontin (OPN) is a considerable and multifunctional extracellular matrix phosphoglycoprote-in. Recent studies have shown that OPN is overexpressed in a variety of cancers, including lung cancer, breast cancer, colorectal cancer, stomach cancer, ovarian cancer, melanoma and mesothelioma and so on. The fact that it interacts with multiple cell surface receptors which are ubiquitously expressed makes it an active player in many physiological and pathological processes, mainly involving the malignant transformation, invasion, metastasis and development etc. of many kinds of cancers. Even someone posed that OPN can be regarded as a target for molecular targeted therapy of many kinds of tumors. By now the expression of OPN in tumor tissue of NPC and its significance remain to be elucidated.
Purpose:To investigate the expression situation of OPN in NPC tissue specimens and approach its significance in NPC; to provide reference index and academic basis for the early diagnosis and clinical treatment of NPC.
Experimental Design, Material and Methods:Cross-sectional studies were conducted involving nasopharyngeal carcinoma, chronic nasopharyngitis and adjacent non-cancerous tissues. Semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to measure messenger RNA of OPN relative expression in fresh frigorific tissues and messenger RNA content was quantitatively determined by image analysis technique; the extent, intensity and localization of OPN expression in paraffin-embedded tissue sections were evaluated with immunohistochemistry (IHC). The relationships of OPN mRNA and OPN protein expression to clinical and pathologic parameters of NPC patients were statistically analyzed. We also used western blotting to (WB) detect the expression situation of OPN protein in 12 pairs cancerous and adjacent non-cancerous tissues paired samples.
Results:From the results of semi-quantitative RT-PCR we obtained the mean (±standard deviation) (x±SD) for OPN/GAPDH(mRNA gray scale value) for OPN expression in 44 nasopharyngeal carcinoma tissues is 0.80 (±0.24) compared with 0.32 (±0.18) in 15 chronic nasopharyngitis. There was statistical significance between them (P<0.05). IHC showed that the staining of OPN was mainly located in the cytoplasm of tumor cells. The positive ratio of OPN in the tissue samples from 67 patients with nasopharyngeal carcinoma (88.1%) significantly higher the one in 21 cases chronic nasopharyngitis (28.6%) (P<0.05). Statistical analyses of the two results above displayed the expression of both OPN mRNA and OPN had nothing to do with age and sex (P>0.05), but associated with T, N and clinical stages of NPC (P<0.05). Osteopontin levels in cancerous tissues were higher than those in corresponding adjacent non-cancerous tissues and the means of OPN/β-Actin (gray scale value) are 0.83 (±0.16) vs0.51 (±0.21).There was significant difference (P<0.05).
Conclusions:The results in our studies suggested that OPN mRNA and OPN protein were overexpressed in NPC. We supposed they may be involved in the malignant transformation of NPC.The strong correlation between OPN mRNA and OPN protein expression and pathological parameters of NPC indicated OPN may play a part in the invasion, metastasis and progression of NPC.
目的：研究OPN在NPC组织标本中表达情况并且探讨其在NPC中的意义；为NPC的早期诊断和临床治疗提供参考指标和理论基础。
试验设计、材料和方法：用横向调查的方法对NPC、慢性鼻咽炎组织和癌旁非癌组织进行研究。用半定量逆转录多聚酶链式反应(RT-PCR)的方法测定OPN mRNA在新鲜的冰冻组织中的相对表达,mRNA的含量用图像分析技术来定量；用免疫组织化学法(IHC)对石蜡包埋的组织切片中OPN的表达的程度、强度和定位进行评估。统计分析OPN mRNA和OPN蛋白的表达和NPC患者临床参数之间的关系。我们还用蛋白印迹法(WB)检测了12对NPC癌组织和癌旁非癌组织的配对标本中OPN蛋白的表达情况。
结果：从半定量RT-PCR的结果中我们得到OPN/GAPDH(mRNA灰度值)的均数(±标准差)在44例NPC组织中为0.80(±0.24),相比之下15例慢性炎症组织中仅为0.32(±0.18),二组之间有统计学意义(P<0.05)。IHC染色显示OPN蛋白主要定位于肿瘤细胞的细胞浆中,其阳性表达率在67例NPC组织中(88.1%%)显著高于21例慢性鼻咽炎组织中的阳性率(28.6%)(P<0.05)。对以上两个结果统计学分析显示OPN mRNA和OPN蛋白的表达均和年龄和性别无关(P>0.05),与肿瘤的T、N和临床分期有关(P<0.05)。WB结果显示OPN蛋白的表达水平在癌组织中高于相对应的癌旁非癌组织中的表达,平均OPN/β-Actin(灰度值)分别为0.83(±0.16)和0.51(±0.21),二组有显著差异(P<0.05)。
结论：我们的研究结果表明OPN mRNA和OPN蛋白在NPC组织中过度表达,推测它可能参与了NPC的恶性转化；OPN mRNA和OPN蛋白的表达和NPC的临床参数密切相关,推测它在NPC的侵袭、转移和进展中起到某种作用。
Context:Nasopharyngeal carcinoma (NPC) is a malignant tumor originating in the nasopharynx, it differs overwhelmingly from other tumors of the head and neck in its causes, occurrence, progression, and treatment. It is vastly more common in southern regions of China than elsewhere. The pathogenesis of nasopharyngeal carcinoma is a complicated process principally involving genetic predisposition, Epstein-Bar Virus infection and environmental factors etc.. However, there are many specific pathogenesis are unclear. Osteopontin (OPN) is a considerable and multifunctional extracellular matrix phosphoglycoprote-in. Recent studies have shown that OPN is overexpressed in a variety of cancers, including lung cancer, breast cancer, colorectal cancer, stomach cancer, ovarian cancer, melanoma and mesothelioma and so on. The fact that it interacts with multiple cell surface receptors which are ubiquitously expressed makes it an active player in many physiological and pathological processes, mainly involving the malignant transformation, invasion, metastasis and development etc. of many kinds of cancers. Even someone posed that OPN can be regarded as a target for molecular targeted therapy of many kinds of tumors. By now the expression of OPN in tumor tissue of NPC and its significance remain to be elucidated.
Purpose:To investigate the expression situation of OPN in NPC tissue specimens and approach its significance in NPC; to provide reference index and academic basis for the early diagnosis and clinical treatment of NPC.
Experimental Design, Material and Methods:Cross-sectional studies were conducted involving nasopharyngeal carcinoma, chronic nasopharyngitis and adjacent non-cancerous tissues. Semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to measure messenger RNA of OPN relative expression in fresh frigorific tissues and messenger RNA content was quantitatively determined by image analysis technique; the extent, intensity and localization of OPN expression in paraffin-embedded tissue sections were evaluated with immunohistochemistry (IHC). The relationships of OPN mRNA and OPN protein expression to clinical and pathologic parameters of NPC patients were statistically analyzed. We also used western blotting to (WB) detect the expression situation of OPN protein in 12 pairs cancerous and adjacent non-cancerous tissues paired samples.
Results:From the results of semi-quantitative RT-PCR we obtained the mean (±standard deviation) (x±SD) for OPN/GAPDH(mRNA gray scale value) for OPN expression in 44 nasopharyngeal carcinoma tissues is 0.80 (±0.24) compared with 0.32 (±0.18) in 15 chronic nasopharyngitis. There was statistical significance between them (P<0.05). IHC showed that the staining of OPN was mainly located in the cytoplasm of tumor cells. The positive ratio of OPN in the tissue samples from 67 patients with nasopharyngeal carcinoma (88.1%) significantly higher the one in 21 cases chronic nasopharyngitis (28.6%) (P<0.05). Statistical analyses of the two results above displayed the expression of both OPN mRNA and OPN had nothing to do with age and sex (P>0.05), but associated with T, N and clinical stages of NPC (P<0.05). Osteopontin levels in cancerous tissues were higher than those in corresponding adjacent non-cancerous tissues and the means of OPN/β-Actin (gray scale value) are 0.83 (±0.16) vs0.51 (±0.21).There was significant difference (P<0.05).
Conclusions:The results in our studies suggested that OPN mRNA and OPN protein were overexpressed in NPC. We supposed they may be involved in the malignant transformation of NPC.The strong correlation between OPN mRNA and OPN protein expression and pathological parameters of NPC indicated OPN may play a part in the invasion, metastasis and progression of NPC.
引文
[1]王荣光,郭宝煌,主译； 尹怀信,叶伟林,主编.鼻咽癌.北京：中国协和医科大学出版社,2002.
[2]Ho JHC. An epidemiologic and clinical study of nasopharyn-geal carcinoma. Int J Radiat Oncol Biol Phys,1978,4:183-205.
[3]Heng DM, Wee J, Fong KW, et al. Prognostic factors in 677 patients in Singapore with nondisseminated nasopharyngeal carcinoma. Cancer,1999, 86(10):1912-20.
[4]Rittling SR, Chambers AF. Role of osteopontin in tumor progression. Br J Cancer,2004,90 (10):1877-81.
[5]Le QT, Sutphin PD, Raychaudhuri S, et al. Identification of osteopontin as a prognostic plasma marker for head and neck squamous cell carcinomas. Clin Cancer Res,2003,9:59-67.
[6]Petrik D, Lavori PW, Cao H, et al. Plasma osteopontin is an independent prognostic marker for head and neck cancers. J Clin Oncol,2006,24:5291-7.
[7]Matsuzaki H, Shima K, Muramatsu T, et al. Osteopontin as biomarker in early invasion by squamous cell carcinoma in tongue. J Oral Pathol Med, 2007,36:30-4.
[8]Yang GH, Fan J, Xu Y, et al. Osteopontin combined with CD44, a novel prognostic biomarker for patients with hepatocellular carcinoma undergoing curative resection. Oncologist,2008,13(11):1155-65.
[9]黄文林.肿瘤分子靶向治疗.北京：人民卫生出版社,2009.
[10]Weber GF. The metastasis gene osteopontin:a candidate target for cancer therapy. Biochim Biophys Acta,2001,1552:61-85,
[11]Sodek J, Ganss B, McKee MD. Osteopontin. Crit Rev Oral Biol Med,2000, 11:279-303.
[12]Denhardt DT, Giachelli CM, Rittling SR. Role of osteopontin in cellular signaling and toxicant injury. Annu Rev Pharmacol Toxicol,2001b,41: 723-49.
[13]Sodek J, Batista Da, Silva AP, et al. Osteopontin and mucosal protection. J Dent Res.2006,85:404-15.
[14]Ashkar S, Weber GF, Panoutsakopoulou V, et al. Eta-1 (osteopontin):an early component of type-1 (cell-mediated) immunity. Science,2000, 287:860-4.
[15]Senger DR. Wirth DF, Hynes RO. Transformed mammalian cells secrete specific proteins and phosphoproteins. Cell,1979,16:885-93.
[16]Franzen A, Heinegrad D. Isolation and characterization of two sialoproteins present only in bone calcified matrix. Biochem J,1985,232:715-24.
[17]Coppola D, Szabo M, Boulware D, et al. Correla-tion of osteopontin protein expression and pathological stage across a wide variety of tumor histologies. Clin Cancer Res,2004,10(1 Pt 1):184-90.
[18]Pan HW, Ou YH, Peng SY, et al. Overexpression of osteopontin is associated with intrahepatic metastasis, early recurrence, and poorer prognosis of surgically resected hepatocellular carcinoma. Cancer,2003; 98:119-27.
[19]Higashiyama M, Ito T, Tanaka E, et al. Prognostic significance of osteopontin expression in human gastric carcinoma. Ann Surg Oncol,2007, 14(12):3419-27.
[20]Zhang X, Tsukamoto T, Mizoshita T, et al. Expression of osteopontin and CDX2:indications of phenotypes and prognosis in advanced gastric cancer. Oncol Rep,2009,21(3):609-13.
[21]Patani N, Jouhra F, Jiang W, et al. Osteopontin expression profiles predict pathological and clinical outcome in breast cancer. Anticancer Res,2008; 28(6B):4105-10.
[22]Chien CY, Su CY, Chuang HC, et al. Comprehensive study on the prognostic role of osteopontin expression in oral squamous cell carcinoma. Oral Oncol,2009,45(9):798-802.
[23]Cho H, Kang ES, Kim YT, et al. Diagnostic and prognostic impact of osteopontin expression in endometrial cancer. Cancer Invest,2009, 27(3):313-23.
[24]Song G, Cai QF, Mao YB, et al. Osteopontin promotes ovarian cancer progression and cell survival and increases HIF-1 alpha expression through the PI3-K/Akt pathway. Cancer Sci,2008,99(10):1901-7.
[25]Wu IC, Wu MT, Chou SH, et al. Osteopontin expression in squamous cell cancer of the esophagus. World J Surg,2008,32(9):1989-95.
[26]Likui W, Hong W, Shuwen Z. Clinical significance of the upregulated osteopontin mRNA expression in human colorectal cancer. J Gastrointest Surg,2010 Jan,14(1):74-81.
[27]Wong TS, Kwong DL, Sham J, et al. Elevation of plasma osteopontin level in patients with undifferentiated nasopharyngeal carcinoma. Eur J Surg Oncol,2005,31(50):555-8.
[28]Edwin P. Hui, Fion L, Sung, et al. A study of osteopontin as a plasma hypoxia marker in nasopharyngeal cancer. Proc Amer Assoc Cancer Res, 2006,47:731-5.
[29]朱晓群,叶青海,雷科峰,等.特异性小干扰性RNA降低骨桥蛋白基因表达对肝癌细胞侵袭性的影响.中华肿瘤杂志,2006,28：404-7.
[30]Gong M, Lu Z, Fang G, et al. A small interfering RNA targeting osteopontin as gastric cancer therapeutics. Cancer Lett,2008,208(1):148-59.
[31]Allan AL, George R, Vantyghem SA, et al. Role of the integrin-binding protein osteopontin in lymphatic metastasis of breast cancer. Am J Pathol, 2006,169:233-46.
[32]Jessen KA, Liu SY, Tepper CG, et al. Molecular analysis of metastasis in a polyoma virus middle T mouse model:the role of osteopontin. Breast Cancer Res,2004,6:157-69.
[33]Liaw L, Lindner V,et al. Osteopontin and β3 integrin are coordinately expressed in regenerating endothelium in vivo and stimulate Arg-Gly-Asp-dependent endothelial migration in vitro. Circ Res,1995, 77:665-72.
[34]El-Tanani MK, Campbell FC, Kurisetty V, et al. The regulation and role of osteopontin in malignant transformation and cancer. Cytokine Growth Factor Rev,2006,17(6):463-74.
[35]Rodrigues LR, Teixeira JA, Schmitt FL, et al. The role of osteopontin in tumor progression and metastasis in breast cancer. Cancer Epidemiol Biomarkers Prev,2007,16(6):1087-97.
[36]Sulzbacher I, Birner P, Trieb K, et al. Expression of osteopontin and vascular endothelial growth factor in benign and malignant bone tumors. Virchows Arch,2002,441(4):345-9.
[37]Mimeault M, Batra SK. Interplay of distinct growth factors during epithelial mesenchymal transition of cancer progenitor cells and molecular targeting as novel cancer therapies. Ann Oncol,2007,18 (10):1605-19.
[38]Chakraorty G, Jain S, Patil TV, et al. Down regulation of osteopontin attenuates breast tumor progression in vivo. J Cell Mol Med,2008,12(6A): 2305-18.
[39]Zohar R, Suzuki N, Suzuki K, et al. Intracellular osteopontin is an intergral component of the CD44·ERM complex involved in cell migration. J Cell Physiol,2000,184(1):118-30.
[40]Teramoto H, Castellone MD, Malek RL,et al.Autocrine activation of an osteopontin-CD44-Rac pathway enhances invasion and transformation by H-RasV12. Oncogene,2005,24(3):489-501.
[41]Hirama M, Takahashi F, Takahashi K, et al. Osteopontin overproduced by tumor cells acts as a potent angiogenic factor contributing to tumor growth. Cancer Lett,2003,198:107-17.
[42]Ariztia EV, Subbarao V, Solt DB, et al. Osteopontin contributes to heaptocyte growth factor induced tumor growth and metastasis formation. Exp Cell Res,2003,288(2):257-67.
[43]Chakraborty G, Jain S, Kundu GC. Osteopontin promotes vascular endothelial growth factor dependent breast tumor growth and angiogenesis via autocrine and paracrine mechanisms. Cancer Res,2008,68(1):152-61.
[44]Weber GF. The metastasis gene osteopontin:a candidate target for cancer therapy. Biochim Biophys Acta,2001,28,1552(2):61-85.
[45]Johnston NI, Gunasekharan VK, Ravindranath A, et al. Osteopontin as a target for cancer therapy. Front Biosci,08,13:4361-72.
[1]Coppola D, Szabo M, Boulware D, et al. Correlation of osteopontin protein expression and pathological stage across a wide variety of tumor histologies. Clin Cancer Res,2004,10:184-90.
[2]Xu G, Nie H, Li N, et al. Role of osteopontin in amplification and perpetuation of rheumatoid synovitis. J Clin Invest,2005,115(4):1060-7.
[3]Zheng W, Li R, Pan H, et al. Role of osteopontin in induction of monocyte chemoattractant protein 1 and macrophage inflammatory protein 1 beta through the NF-kappaB and MAPK pathways in rheumatoid arthritis. Arthritis Rheum, 2009,60(7):1957-65.
[4]Ramaiah SK, Rittling S. Pathophysiological role of osteopontin in hepatic inflammation, toxicity, and cancer. Toxicol Sci,2008,103 (1):4-13.
[5]Diao H, Kon S, Iwabuchi K, et al. Osteopontin as a mediator of NKT cell fimction in T cell-mediated liverdiseases. Immtmity,2004,21 (4):539-50.
[6]Kwon HM, Hong BK, Kang TS, et al. Expression of osteopontin in calcified coronary atherosclerotic plaques. J Korean Med Sci,2000,15:485-93.
[7]张永钢,韩梅,温进坤.骨桥蛋白的病理功能.中国老年学杂志,2005,25：230-2.
[8]Senger DR, Wirth DF, Hynes RO. Transformed mammalian cells secrete specific proteins and phosphoproteins. Cell,1979,16:885-93.
[9]Franzen A, Heinegrad D. Isolation and characterization of two sialoproteins present only in bone calcified matrix. Biochem J,1985,232:715-24.
[10]Prince CW. Secondary structure predictions for rat osteopontin. Connect Tissue Res,1989,21:15-20.
[11]Oldberg A, Franzen A, Heinegard D. Cloning and sequence analysis of rat bone sialoprotein(osteopontin)cDN A reveals an Arg-Gly-Asp cell-binding sequence. Proc Natl Acad Sci USA,1986,83 (23):8819-23.
[12]Weber G F.Ashkar S.Glimcher M J. Receptor-ligand interaction between CD44 and osteopontin (Eta-1).1996,271(5248):509-12.
[13]Zhu Y, Denhardt DT, Cao H. Hypoxia upregulates osteopontin expression in NIH 3T3 cells via a Ras activated enhancer. Oncogene,2005,24(43):6555-63.
[14]Rittling SR, Chambers AF.Role of osteopontin in tumour progression.Br J Cancer,2004,90(10):1877-81.
[15]Wai PY, Kuo PC. The role of Osteopontin in tumor metastasis. J Surg Res, 2004,121 (2):228-41.
[16]Rangaswami H, Bulbule A, Kundu GC, et al. Osteopontin:role in cell signaling and cancer progression. Trends Cell Biol,2006,16(2):79-87.
[17]Teramoto H, Castellone MD, Malek RL,et al.Autocrine activation of an osteopontin-CD44-Rac pathway enhances invasion and transformation by H-RasV12. Oncogene,2005,24(3):489-501.
[18]Hirama M, Takahashi F, Takahashi K, et al. Osteopontin overproduced by tumor cells acts as a potent angiogenic factor contributing to tumor growth. Cancer Lett,2003,198:107-17.
[19]Wong T S, Kwong D L, Sham J, et al. Elevation of plasma osteopontin level in patients with undifferentiated nasopharyngeal carcinoma. Eur J Surg Oncol, 2005,31(5):555-8.
[20]Celetti A, Testa D, Staibano S, et al. Overexpression of the cytokine osteopontin identifies aggressive laryngeal squamous cell carcinomas and enhances carcinoma cell proliferation and invasiveness. Clin Cancer Res,2005,11 (22): 8019-27.
[21]Eto M, Kodama S, Nomi N, Uemura N, Suzuki M. Clinical significance of elevated osteopontin levels in head and neck cancer patients. Auris Nasus Larynx,2007,34(3):343-6.
[22]Chien CY, Su CY, et al. Comprehensive study on the prognostic role of osteopontin expression in oral squamous cell carcinoma. Oral Oncol,2009 10:1521-9
[23]Darling MR, Gauthier M, Jackson-Boeters L, et al. Osteopontin expression in salivary gland tumours. Oral Oncol,2006,42(4):363-9.
[24]Chien CY, Su CY, Chuang HC, Fang FM, et al. Clinical significance of osteopontin expression in T1 and T2 tongue cancers. Head Neck,2008, 30(6):776-81.
[25]Nordsmark M, Bentzen SM, Rudat V, et al. Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother Oncol,2005,77:18-24.
[26]Le QT, Sutphin PD, Raychaudhuri S, et al. Identification of osteopontin asa prognostic plasma marker for head and neck squamous cell carcinomas. Clin Cancer Res,2003,9:59-67.
[27]Hui EP, Sung FL, Yu BK, Wong CS, et al. Plasma osteopontin, hypoxia, and response to radiotherapy in nasopharyngeal cancer. Clin Cancer Res,2008,14 (21):7080-7.
[28]Said HM, Katzer A, Flentje M, Vordermark D, et al. Response of the plasma hypoxia marker osteopontin to in vitro hypoxia in human tumor cells. Radiother Oncol.2006,78 (2):230-1.
[2]Ho JHC. An epidemiologic and clinical study of nasopharyn-geal carcinoma. Int J Radiat Oncol Biol Phys,1978,4:183-205.
[3]Heng DM, Wee J, Fong KW, et al. Prognostic factors in 677 patients in Singapore with nondisseminated nasopharyngeal carcinoma. Cancer,1999, 86(10):1912-20.
[4]Rittling SR, Chambers AF. Role of osteopontin in tumor progression. Br J Cancer,2004,90 (10):1877-81.
[5]Le QT, Sutphin PD, Raychaudhuri S, et al. Identification of osteopontin as a prognostic plasma marker for head and neck squamous cell carcinomas. Clin Cancer Res,2003,9:59-67.
[6]Petrik D, Lavori PW, Cao H, et al. Plasma osteopontin is an independent prognostic marker for head and neck cancers. J Clin Oncol,2006,24:5291-7.
[7]Matsuzaki H, Shima K, Muramatsu T, et al. Osteopontin as biomarker in early invasion by squamous cell carcinoma in tongue. J Oral Pathol Med, 2007,36:30-4.
[8]Yang GH, Fan J, Xu Y, et al. Osteopontin combined with CD44, a novel prognostic biomarker for patients with hepatocellular carcinoma undergoing curative resection. Oncologist,2008,13(11):1155-65.
[9]黄文林.肿瘤分子靶向治疗.北京：人民卫生出版社,2009.
[10]Weber GF. The metastasis gene osteopontin:a candidate target for cancer therapy. Biochim Biophys Acta,2001,1552:61-85,
[11]Sodek J, Ganss B, McKee MD. Osteopontin. Crit Rev Oral Biol Med,2000, 11:279-303.
[12]Denhardt DT, Giachelli CM, Rittling SR. Role of osteopontin in cellular signaling and toxicant injury. Annu Rev Pharmacol Toxicol,2001b,41: 723-49.
[13]Sodek J, Batista Da, Silva AP, et al. Osteopontin and mucosal protection. J Dent Res.2006,85:404-15.
[14]Ashkar S, Weber GF, Panoutsakopoulou V, et al. Eta-1 (osteopontin):an early component of type-1 (cell-mediated) immunity. Science,2000, 287:860-4.
[15]Senger DR. Wirth DF, Hynes RO. Transformed mammalian cells secrete specific proteins and phosphoproteins. Cell,1979,16:885-93.
[16]Franzen A, Heinegrad D. Isolation and characterization of two sialoproteins present only in bone calcified matrix. Biochem J,1985,232:715-24.
[17]Coppola D, Szabo M, Boulware D, et al. Correla-tion of osteopontin protein expression and pathological stage across a wide variety of tumor histologies. Clin Cancer Res,2004,10(1 Pt 1):184-90.
[18]Pan HW, Ou YH, Peng SY, et al. Overexpression of osteopontin is associated with intrahepatic metastasis, early recurrence, and poorer prognosis of surgically resected hepatocellular carcinoma. Cancer,2003; 98:119-27.
[19]Higashiyama M, Ito T, Tanaka E, et al. Prognostic significance of osteopontin expression in human gastric carcinoma. Ann Surg Oncol,2007, 14(12):3419-27.
[20]Zhang X, Tsukamoto T, Mizoshita T, et al. Expression of osteopontin and CDX2:indications of phenotypes and prognosis in advanced gastric cancer. Oncol Rep,2009,21(3):609-13.
[21]Patani N, Jouhra F, Jiang W, et al. Osteopontin expression profiles predict pathological and clinical outcome in breast cancer. Anticancer Res,2008; 28(6B):4105-10.
[22]Chien CY, Su CY, Chuang HC, et al. Comprehensive study on the prognostic role of osteopontin expression in oral squamous cell carcinoma. Oral Oncol,2009,45(9):798-802.
[23]Cho H, Kang ES, Kim YT, et al. Diagnostic and prognostic impact of osteopontin expression in endometrial cancer. Cancer Invest,2009, 27(3):313-23.
[24]Song G, Cai QF, Mao YB, et al. Osteopontin promotes ovarian cancer progression and cell survival and increases HIF-1 alpha expression through the PI3-K/Akt pathway. Cancer Sci,2008,99(10):1901-7.
[25]Wu IC, Wu MT, Chou SH, et al. Osteopontin expression in squamous cell cancer of the esophagus. World J Surg,2008,32(9):1989-95.
[26]Likui W, Hong W, Shuwen Z. Clinical significance of the upregulated osteopontin mRNA expression in human colorectal cancer. J Gastrointest Surg,2010 Jan,14(1):74-81.
[27]Wong TS, Kwong DL, Sham J, et al. Elevation of plasma osteopontin level in patients with undifferentiated nasopharyngeal carcinoma. Eur J Surg Oncol,2005,31(50):555-8.
[28]Edwin P. Hui, Fion L, Sung, et al. A study of osteopontin as a plasma hypoxia marker in nasopharyngeal cancer. Proc Amer Assoc Cancer Res, 2006,47:731-5.
[29]朱晓群,叶青海,雷科峰,等.特异性小干扰性RNA降低骨桥蛋白基因表达对肝癌细胞侵袭性的影响.中华肿瘤杂志,2006,28：404-7.
[30]Gong M, Lu Z, Fang G, et al. A small interfering RNA targeting osteopontin as gastric cancer therapeutics. Cancer Lett,2008,208(1):148-59.
[31]Allan AL, George R, Vantyghem SA, et al. Role of the integrin-binding protein osteopontin in lymphatic metastasis of breast cancer. Am J Pathol, 2006,169:233-46.
[32]Jessen KA, Liu SY, Tepper CG, et al. Molecular analysis of metastasis in a polyoma virus middle T mouse model:the role of osteopontin. Breast Cancer Res,2004,6:157-69.
[33]Liaw L, Lindner V,et al. Osteopontin and β3 integrin are coordinately expressed in regenerating endothelium in vivo and stimulate Arg-Gly-Asp-dependent endothelial migration in vitro. Circ Res,1995, 77:665-72.
[34]El-Tanani MK, Campbell FC, Kurisetty V, et al. The regulation and role of osteopontin in malignant transformation and cancer. Cytokine Growth Factor Rev,2006,17(6):463-74.
[35]Rodrigues LR, Teixeira JA, Schmitt FL, et al. The role of osteopontin in tumor progression and metastasis in breast cancer. Cancer Epidemiol Biomarkers Prev,2007,16(6):1087-97.
[36]Sulzbacher I, Birner P, Trieb K, et al. Expression of osteopontin and vascular endothelial growth factor in benign and malignant bone tumors. Virchows Arch,2002,441(4):345-9.
[37]Mimeault M, Batra SK. Interplay of distinct growth factors during epithelial mesenchymal transition of cancer progenitor cells and molecular targeting as novel cancer therapies. Ann Oncol,2007,18 (10):1605-19.
[38]Chakraorty G, Jain S, Patil TV, et al. Down regulation of osteopontin attenuates breast tumor progression in vivo. J Cell Mol Med,2008,12(6A): 2305-18.
[39]Zohar R, Suzuki N, Suzuki K, et al. Intracellular osteopontin is an intergral component of the CD44·ERM complex involved in cell migration. J Cell Physiol,2000,184(1):118-30.
[40]Teramoto H, Castellone MD, Malek RL,et al.Autocrine activation of an osteopontin-CD44-Rac pathway enhances invasion and transformation by H-RasV12. Oncogene,2005,24(3):489-501.
[41]Hirama M, Takahashi F, Takahashi K, et al. Osteopontin overproduced by tumor cells acts as a potent angiogenic factor contributing to tumor growth. Cancer Lett,2003,198:107-17.
[42]Ariztia EV, Subbarao V, Solt DB, et al. Osteopontin contributes to heaptocyte growth factor induced tumor growth and metastasis formation. Exp Cell Res,2003,288(2):257-67.
[43]Chakraborty G, Jain S, Kundu GC. Osteopontin promotes vascular endothelial growth factor dependent breast tumor growth and angiogenesis via autocrine and paracrine mechanisms. Cancer Res,2008,68(1):152-61.
[44]Weber GF. The metastasis gene osteopontin:a candidate target for cancer therapy. Biochim Biophys Acta,2001,28,1552(2):61-85.
[45]Johnston NI, Gunasekharan VK, Ravindranath A, et al. Osteopontin as a target for cancer therapy. Front Biosci,08,13:4361-72.
[1]Coppola D, Szabo M, Boulware D, et al. Correlation of osteopontin protein expression and pathological stage across a wide variety of tumor histologies. Clin Cancer Res,2004,10:184-90.
[2]Xu G, Nie H, Li N, et al. Role of osteopontin in amplification and perpetuation of rheumatoid synovitis. J Clin Invest,2005,115(4):1060-7.
[3]Zheng W, Li R, Pan H, et al. Role of osteopontin in induction of monocyte chemoattractant protein 1 and macrophage inflammatory protein 1 beta through the NF-kappaB and MAPK pathways in rheumatoid arthritis. Arthritis Rheum, 2009,60(7):1957-65.
[4]Ramaiah SK, Rittling S. Pathophysiological role of osteopontin in hepatic inflammation, toxicity, and cancer. Toxicol Sci,2008,103 (1):4-13.
[5]Diao H, Kon S, Iwabuchi K, et al. Osteopontin as a mediator of NKT cell fimction in T cell-mediated liverdiseases. Immtmity,2004,21 (4):539-50.
[6]Kwon HM, Hong BK, Kang TS, et al. Expression of osteopontin in calcified coronary atherosclerotic plaques. J Korean Med Sci,2000,15:485-93.
[7]张永钢,韩梅,温进坤.骨桥蛋白的病理功能.中国老年学杂志,2005,25：230-2.
[8]Senger DR, Wirth DF, Hynes RO. Transformed mammalian cells secrete specific proteins and phosphoproteins. Cell,1979,16:885-93.
[9]Franzen A, Heinegrad D. Isolation and characterization of two sialoproteins present only in bone calcified matrix. Biochem J,1985,232:715-24.
[10]Prince CW. Secondary structure predictions for rat osteopontin. Connect Tissue Res,1989,21:15-20.
[11]Oldberg A, Franzen A, Heinegard D. Cloning and sequence analysis of rat bone sialoprotein(osteopontin)cDN A reveals an Arg-Gly-Asp cell-binding sequence. Proc Natl Acad Sci USA,1986,83 (23):8819-23.
[12]Weber G F.Ashkar S.Glimcher M J. Receptor-ligand interaction between CD44 and osteopontin (Eta-1).1996,271(5248):509-12.
[13]Zhu Y, Denhardt DT, Cao H. Hypoxia upregulates osteopontin expression in NIH 3T3 cells via a Ras activated enhancer. Oncogene,2005,24(43):6555-63.
[14]Rittling SR, Chambers AF.Role of osteopontin in tumour progression.Br J Cancer,2004,90(10):1877-81.
[15]Wai PY, Kuo PC. The role of Osteopontin in tumor metastasis. J Surg Res, 2004,121 (2):228-41.
[16]Rangaswami H, Bulbule A, Kundu GC, et al. Osteopontin:role in cell signaling and cancer progression. Trends Cell Biol,2006,16(2):79-87.
[17]Teramoto H, Castellone MD, Malek RL,et al.Autocrine activation of an osteopontin-CD44-Rac pathway enhances invasion and transformation by H-RasV12. Oncogene,2005,24(3):489-501.
[18]Hirama M, Takahashi F, Takahashi K, et al. Osteopontin overproduced by tumor cells acts as a potent angiogenic factor contributing to tumor growth. Cancer Lett,2003,198:107-17.
[19]Wong T S, Kwong D L, Sham J, et al. Elevation of plasma osteopontin level in patients with undifferentiated nasopharyngeal carcinoma. Eur J Surg Oncol, 2005,31(5):555-8.
[20]Celetti A, Testa D, Staibano S, et al. Overexpression of the cytokine osteopontin identifies aggressive laryngeal squamous cell carcinomas and enhances carcinoma cell proliferation and invasiveness. Clin Cancer Res,2005,11 (22): 8019-27.
[21]Eto M, Kodama S, Nomi N, Uemura N, Suzuki M. Clinical significance of elevated osteopontin levels in head and neck cancer patients. Auris Nasus Larynx,2007,34(3):343-6.
[22]Chien CY, Su CY, et al. Comprehensive study on the prognostic role of osteopontin expression in oral squamous cell carcinoma. Oral Oncol,2009 10:1521-9
[23]Darling MR, Gauthier M, Jackson-Boeters L, et al. Osteopontin expression in salivary gland tumours. Oral Oncol,2006,42(4):363-9.
[24]Chien CY, Su CY, Chuang HC, Fang FM, et al. Clinical significance of osteopontin expression in T1 and T2 tongue cancers. Head Neck,2008, 30(6):776-81.
[25]Nordsmark M, Bentzen SM, Rudat V, et al. Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother Oncol,2005,77:18-24.
[26]Le QT, Sutphin PD, Raychaudhuri S, et al. Identification of osteopontin asa prognostic plasma marker for head and neck squamous cell carcinomas. Clin Cancer Res,2003,9:59-67.
[27]Hui EP, Sung FL, Yu BK, Wong CS, et al. Plasma osteopontin, hypoxia, and response to radiotherapy in nasopharyngeal cancer. Clin Cancer Res,2008,14 (21):7080-7.
[28]Said HM, Katzer A, Flentje M, Vordermark D, et al. Response of the plasma hypoxia marker osteopontin to in vitro hypoxia in human tumor cells. Radiother Oncol.2006,78 (2):230-1.