蛋白水解诱导因子核心肽mRNA在食管癌组织中的表达
摘要
目的
恶病质是一种以短期内体重下降,脂肪和肌肉群进行性消耗为特征,即出现碳水化合物、脂质和蛋白质代谢的变化,同时伴有厌食、贫血、浮肿、衰竭等表现的综合征。引发恶病质的具体机制不是很清楚。大多数进展期恶性肿瘤的普遍表现是癌性恶病质的发生发展,它是这些疾病死亡的一个重要的独立因素。在恶病质病人中，骨骼肌萎缩是由于蛋白代谢增加和蛋白合成的减少,两种情况可能同时发生,从而造成严重的肌肉萎。引发恶病质的具体机制不是很清楚。在癌性恶病质中组织代谢所涉及的因子,包括肿瘤坏死因子-α(TNF-α),白细胞介素-1(IL-1),白介素-6(IL-6),干扰素-γ(IFN-γ),脂解因子锌α2-糖蛋白,肿瘤特殊产物。但有研究显示血清中TNF-α、IL-1、IL-6和IFN-γ都与患有进展期和终末期癌症的病人的体重减轻无明确联系。蛋白水解诱导因子(proteolysis-inducing factor, PIF),一种与恶病质病人的体重减轻有关的因子。最开始从MAC16肿瘤模型中分离,人类PIF的同系物随后在体重减轻的恶病质病人的尿液中检出。在体内和体外,PIF都可以引起骨骼肌的蛋白水解。PIF为糖基化的蛋白,分子量约为24kDa,包括一段4kDa的核心肽和碳水化合物残基。一些胃肠道的肿瘤和肿瘤细胞系过量表达PIF蛋白。
人类来源的PIF定义为人类恶病质相关蛋白(HCAP),在前列腺癌患者检测出它的表达。实验证明仅在前列腺癌细胞系中检测出HCAPmRNA的表达,而在间质组织中没有表达。把这些癌细胞植入小鼠体内,小鼠的体重减轻明显和HCAPmRNA的表达有关。PIF核心肽的基因定位于12号染色体(12q13.1),并于正常皮肤、乳腺和脑组织以及源于原发和转移肿瘤的各种癌细胞中鉴定出它的转录物。本研究主要通过半定量RT-PCR的方法,检测PIF-CP mRNA在食管鳞状细胞癌肿瘤组织、癌旁组织以及正常组织中的表达情况以及PIF-CP mRNA的表达与肿瘤分化和肿瘤临床分期的关系。
方法
提取60例食管癌患者肿瘤组织和癌旁组织的总RNA,同时提取11例食管良性疾病患者的正常食管组织的总RNA。通过测量RNA纯度及浓度,用半定量RT-PCR的方法检测PIF核心肽基因mRNA在食管鳞状细胞癌肿瘤组织癌旁组织以及食管良性疾病手术切除的正常食管组织的表达。根据Genbank人类来源的PIF基因序列(AY590150)设计特异性引物,取10μlPCR产物经1.2%琼脂糖凝胶电泳,GeneFander染色鉴定,凝胶成像分析系统进行拍照、分析。通过软件测量灰度值。以PIF-CP与β-actin之比,作为PIF-CP mRNA的相对的表达量。
结果
用半定量RT-PCR的方法,检测食管癌患者肿瘤组织和癌旁组织及食管良性疾病患者手术切除的正常食道组织的PIF-CP基因的mRNA表达,发现肿瘤组织与癌旁组织中表达水平无明显差异(P>0.05)。尽管在正常组织中也检测出PIF-CP mRNA的表达,但是与肿瘤患者的肿瘤组织和癌旁组织相比表达的水平非常低(P<0.05)。PIF-CP基因mRNA的表达在食管癌的不同分期没有差异(P>0.05)而且与肿瘤的分化也无相关性(P>0.05)。
结论
PIF-CP基因mRNA在食管癌患者肿瘤组织和正常食管组织的表达没有差异,但是与食管良性疾病的食管组织中PIF-CP基因mRNA的表达有差别。PIF-CP基因mRNA的表达与肿瘤分期和分化没有相关性。
Objective
Cachexia is a form of weight loss decresed, fat and muscle groups progressing consumed, which is the syndrome that carbohydrate, lipid and protein metabolism accompanied with anorexia, anemia, edema, exhaustion and other manifestations. The most common manifestation of advanced cancers is occurrence and development of cachexia, which is an important independent factor that induced the death of the cancers. In cachexia patients, skeletal muscle atrophy is due to increased metabolism of protein and inhibited synthesis of protein, which may occur simultaneously to result in severe muscle atrophy. The mechanism of cachexia-induced is not clear. In the factors which involved in the metabolism of cancer cachexia, including tumor necrosis factor-α(TNF-α). interleukin -1 (IL-1), interleukin -6 (IL-6). interferon-γ(IFN-γ), lipolytic factor zincα2-glycoprotein, and tumor specific products. However, studies have shown that serum TNF-α, IL-1, IL-6 and IFN-γare not related to weight loss of people with advanced and end-stage cancer patients. Proteolysis-inducing factor (PIF) is a kind of factors that is related to weight loss, which was initially isolated from the MAC 16 tumor model, and then a homologue of human PIF subsequent was found in the urine of patients who had weight loss. PIF can both cause skeletal muscle proteolysis in vivo and in vitro. PIF is a glycation of proteins with 24000kDa, including a core peptide with 4kDa and carbohydrate residues. A number of gastrointestinal tumors and tumor cell lines can express PIF protein. The human source of PIF is defined the human cachexia associated protein (HCAP), which core peptide gene is located on chromosome 12 (12q 13.1). It can identify the transcripts in normal skin, breast, brain tissue, primary and metastatic tumors of various cancer cells.
Materials and Methods
Extraction the total mRNA of 60 patients with esophageal cancer tumor tissue and normal esophageal tissue. while extraction the normal esophageal tissues of 11 cases of patients with benign esophageal disease,. Using semi-quantitative RT-PCR method to detect the expression of PIF core peptide mRNA in esophageal cancer and in normal esophageal tissue.
Results
The expression of PIF-CP gene mRNA in tumor tissues and in normal tissues,. There is no significantly difference of the expression of PIF-CP gene mRNA between the two (P＞0.05). Simultaneous detection the expression of mRNA in 11 cases with benign esophageal disease organizations, detecting the expression of PIF-CP mRNA, but in a very low expression level compared with the tumor tissues(P＜0.05). There are no differences of the expression of PIF-CP gene mRNA neither in different stages nor in tumor differentiation of esophageal cancer (P＞0.05).
Conclusion
There is no significantly difference in the expression of PIF-CP gene mRNA in esophageal carcinomas and normal esophageal tissues, but have differences between normal or benign esophageal disease and esophageal tissue. There is no relationship between the expression of PIF-CP gene mRNA and tumor stage and differentiation.
恶病质是一种以短期内体重下降,脂肪和肌肉群进行性消耗为特征,即出现碳水化合物、脂质和蛋白质代谢的变化,同时伴有厌食、贫血、浮肿、衰竭等表现的综合征。引发恶病质的具体机制不是很清楚。大多数进展期恶性肿瘤的普遍表现是癌性恶病质的发生发展,它是这些疾病死亡的一个重要的独立因素。在恶病质病人中，骨骼肌萎缩是由于蛋白代谢增加和蛋白合成的减少,两种情况可能同时发生,从而造成严重的肌肉萎。引发恶病质的具体机制不是很清楚。在癌性恶病质中组织代谢所涉及的因子,包括肿瘤坏死因子-α(TNF-α),白细胞介素-1(IL-1),白介素-6(IL-6),干扰素-γ(IFN-γ),脂解因子锌α2-糖蛋白,肿瘤特殊产物。但有研究显示血清中TNF-α、IL-1、IL-6和IFN-γ都与患有进展期和终末期癌症的病人的体重减轻无明确联系。蛋白水解诱导因子(proteolysis-inducing factor, PIF),一种与恶病质病人的体重减轻有关的因子。最开始从MAC16肿瘤模型中分离,人类PIF的同系物随后在体重减轻的恶病质病人的尿液中检出。在体内和体外,PIF都可以引起骨骼肌的蛋白水解。PIF为糖基化的蛋白,分子量约为24kDa,包括一段4kDa的核心肽和碳水化合物残基。一些胃肠道的肿瘤和肿瘤细胞系过量表达PIF蛋白。
人类来源的PIF定义为人类恶病质相关蛋白(HCAP),在前列腺癌患者检测出它的表达。实验证明仅在前列腺癌细胞系中检测出HCAPmRNA的表达,而在间质组织中没有表达。把这些癌细胞植入小鼠体内,小鼠的体重减轻明显和HCAPmRNA的表达有关。PIF核心肽的基因定位于12号染色体(12q13.1),并于正常皮肤、乳腺和脑组织以及源于原发和转移肿瘤的各种癌细胞中鉴定出它的转录物。本研究主要通过半定量RT-PCR的方法,检测PIF-CP mRNA在食管鳞状细胞癌肿瘤组织、癌旁组织以及正常组织中的表达情况以及PIF-CP mRNA的表达与肿瘤分化和肿瘤临床分期的关系。
方法
提取60例食管癌患者肿瘤组织和癌旁组织的总RNA,同时提取11例食管良性疾病患者的正常食管组织的总RNA。通过测量RNA纯度及浓度,用半定量RT-PCR的方法检测PIF核心肽基因mRNA在食管鳞状细胞癌肿瘤组织癌旁组织以及食管良性疾病手术切除的正常食管组织的表达。根据Genbank人类来源的PIF基因序列(AY590150)设计特异性引物,取10μlPCR产物经1.2%琼脂糖凝胶电泳,GeneFander染色鉴定,凝胶成像分析系统进行拍照、分析。通过软件测量灰度值。以PIF-CP与β-actin之比,作为PIF-CP mRNA的相对的表达量。
结果
用半定量RT-PCR的方法,检测食管癌患者肿瘤组织和癌旁组织及食管良性疾病患者手术切除的正常食道组织的PIF-CP基因的mRNA表达,发现肿瘤组织与癌旁组织中表达水平无明显差异(P>0.05)。尽管在正常组织中也检测出PIF-CP mRNA的表达,但是与肿瘤患者的肿瘤组织和癌旁组织相比表达的水平非常低(P<0.05)。PIF-CP基因mRNA的表达在食管癌的不同分期没有差异(P>0.05)而且与肿瘤的分化也无相关性(P>0.05)。
结论
PIF-CP基因mRNA在食管癌患者肿瘤组织和正常食管组织的表达没有差异,但是与食管良性疾病的食管组织中PIF-CP基因mRNA的表达有差别。PIF-CP基因mRNA的表达与肿瘤分期和分化没有相关性。
Objective
Cachexia is a form of weight loss decresed, fat and muscle groups progressing consumed, which is the syndrome that carbohydrate, lipid and protein metabolism accompanied with anorexia, anemia, edema, exhaustion and other manifestations. The most common manifestation of advanced cancers is occurrence and development of cachexia, which is an important independent factor that induced the death of the cancers. In cachexia patients, skeletal muscle atrophy is due to increased metabolism of protein and inhibited synthesis of protein, which may occur simultaneously to result in severe muscle atrophy. The mechanism of cachexia-induced is not clear. In the factors which involved in the metabolism of cancer cachexia, including tumor necrosis factor-α(TNF-α). interleukin -1 (IL-1), interleukin -6 (IL-6). interferon-γ(IFN-γ), lipolytic factor zincα2-glycoprotein, and tumor specific products. However, studies have shown that serum TNF-α, IL-1, IL-6 and IFN-γare not related to weight loss of people with advanced and end-stage cancer patients. Proteolysis-inducing factor (PIF) is a kind of factors that is related to weight loss, which was initially isolated from the MAC 16 tumor model, and then a homologue of human PIF subsequent was found in the urine of patients who had weight loss. PIF can both cause skeletal muscle proteolysis in vivo and in vitro. PIF is a glycation of proteins with 24000kDa, including a core peptide with 4kDa and carbohydrate residues. A number of gastrointestinal tumors and tumor cell lines can express PIF protein. The human source of PIF is defined the human cachexia associated protein (HCAP), which core peptide gene is located on chromosome 12 (12q 13.1). It can identify the transcripts in normal skin, breast, brain tissue, primary and metastatic tumors of various cancer cells.
Materials and Methods
Extraction the total mRNA of 60 patients with esophageal cancer tumor tissue and normal esophageal tissue. while extraction the normal esophageal tissues of 11 cases of patients with benign esophageal disease,. Using semi-quantitative RT-PCR method to detect the expression of PIF core peptide mRNA in esophageal cancer and in normal esophageal tissue.
Results
The expression of PIF-CP gene mRNA in tumor tissues and in normal tissues,. There is no significantly difference of the expression of PIF-CP gene mRNA between the two (P＞0.05). Simultaneous detection the expression of mRNA in 11 cases with benign esophageal disease organizations, detecting the expression of PIF-CP mRNA, but in a very low expression level compared with the tumor tissues(P＜0.05). There are no differences of the expression of PIF-CP gene mRNA neither in different stages nor in tumor differentiation of esophageal cancer (P＞0.05).
Conclusion
There is no significantly difference in the expression of PIF-CP gene mRNA in esophageal carcinomas and normal esophageal tissues, but have differences between normal or benign esophageal disease and esophageal tissue. There is no relationship between the expression of PIF-CP gene mRNA and tumor stage and differentiation.
引文
1 Todorov P,Tisdale MJ(1996b) Induction of muscle protein degradation and weight loss by a tumour product. cancer Res 56:1256-1261. 2 Wang Z, Corey E, Hass GM, Higano CS,et al.(2003). Expression of the human cachexia-associated protein(HCAP) in prostate cancer and in a prostate cancer animal model of cachexia. Int. J. Cancer 105:123-129. 3 Watchorn TM, Waddell ID, Dowidar N, and Ross JA. (2001)Proteolysis-inducing factor regulates hepatic gene expression via transcription factors NF-kB and STAT3. FASEB J 15:562-564. 4 Watchorn TM, Dowidar N, Dejong CH, Waddell ID, Garden OJ, Ross JA The cachectic mediator proteolysis inducing factor activates NF-kappaB and STAT3 in human Kupffer cells and monocytes Int J Oncol.2005 Oct;27(4):1105-1111. 5 Whitehouse AS,Khal J, Tisdale MJ. Induction of protein catabolism in myotubes by 15(S)-hydroxyeicosatetraenoic acid through increased expression of the ubiquitin-proteasome pathway [J]. Br J Cancer,2003,89(4):737-745. 6 Whitehouse AS, Tisdale MJ Increased expression of the ubiquitin-proteasome pathway in murine myotubes by proteolysis-inducing factor (PIF) is associated with activation of the transcription factor NF-kappaB Br J Cancer,2003 Sep 15;89(6):1116-22. 7 Wigmore SJ, Fearon KCH, Sangster K, et al (2002) Cytokine regulation of constitutive production of interleukin-8 and -6 by human pancreatic cancer cell lines and serum cytoline concentrations in patients with pancreatic cancer. Int J Oncol 21:881-886. 8 Smith HJ,Tisdale MJ. Induction of apoptosis by a cachectic-factor in Murine myotube and inhibition by eicosapentaenoic acid[J]. Apoptosis,2003,8(2):161-169. 9 MCC Gomes-Marcondes,HJ Smith, JC Cooper and MJ Tisdale Development of an in-vitro model system to investigate the mechanism of muscle protein catabolism induced by proteolysis-inducing factor. British Journal of Cancer (2002) 86,1628-1633. 10 Helen J. Smith, Pradip Mukerji, and Michael J. Tisdale Attenuation of proteasome-Induced Proteolysis in skeletal muscle by B-Hydroxy-B-Methylbutyrate in cancer-induced muscle loss.Cancer Res 2005;65(1):277-283. 11 Whitehouse AS, Tisdale MJ Increased expression of the ubiquitin-proteasome pathway in murine myotubes by proteolysis-inducing factor (PIF) is associated with activation of the transcription factor NF-kappaB Br J Cancer,2003 Sep 15;89(6):1116-1122. 12 A.Jatoi, N.Foster, B.Wieland, et al The proteolysis-inducing factor:in search of its clinical relevance in patients with metastatic gastric/esophageal cancer. Diseases of the Esophagus (2006) 19,241-247
13 Bossola M,Muscaritoli M,Costelli P,et al Increased muscle proteasome activity correlates with disease severity in gastric cancer patients[J]. Ann Surg,2003,237(3):384-389.
14 Cabal-Manzano R, Bhargava P. Torres-Duarte A, etal Proteolysis inducing factor is expressed in tumours of patients with gastrointestinal cancers and correlates with weight loss[J]. Br J Cancer,2001,84(12):1599-1601
15 Cariuk P,Lorite MJ, Todorov PT,et al Induction of cachexia in mice by a product isolated from the urine of cachectic cancer patients[J]. Br J Cancer,1997,76(5):606-613
1 A.Jatoi, N.Foster, B.Wieland, et al The proteolysis-inducing factor: in search of its clinical relevance in patients with metastatic gastric/esophageal cancer. Diseases of the Esophagus (2006) 19,241-247
2 Bossola M,Muscaritoli M,Costelli P,et al Increased muscle proteasome activity correlates with disease severity in gastric cancer patients[J]. Ann Surg,2003,237(3):384-389.
3 Cabal-Manzano R, Bhargava P. Torres-Duarte A, etal Proteolysis inducing factor is expressed in tumours of patients with gastrointestinal cancers and correlates with weight loss[J]. Br J Cancer,2001,84(12):1599-1601
4 Cariuk P,Lorite MJ, Todorov PT,et al Induction of cachexia in mice by a product isolated from the urine of cachectic cancer patients[J]. Br J Cancer,1997,76(5):606-613
5 Cummings, R. D., kornfeld, S., Schneider, W. J., Hobgood, K. K.,Tolleshaug, H., Brown, M. S., and Goldstein, J. L. (1983) J. Biol. Chem.258,15261-15273
6 Cunningham TJ, Jing H, Akerblom I, Morgan R, et al. (2002). Idengtification of the human cDNA for new survival/evasion peptide (DSEP):studies in vitro and in vivo of overexpression by neural cell. Exp. Neurol.177:32-39
7 Deans DA, Wigmore SJ, Gilmour H, Tisdale MJ, etal. (2006). Expression of the proteolysis-inducing factor core peptide mRNA is upregulated in both tumor and adjacent normal tissue in gastro-oesophageal malignancy. Br. J. Cancer 94:731-736
8 Dewys WD, Begg C et al.(1980)Prognostic effect of weight loss prior to chemotherapy in cancer patients.Eastern Cooperative Oncology Group. Am J Med 69:491-497
9 Eley HL, Russell ST,Tisdale MJ Effect of branched-chain amino acids on muscle atrophy in cancer cachexia. Biochem J.2007 Oct 1;407(1):113-20
10 Helen J. Smith, Pradip Mukerji, and Michael J. Tisdale Attenuation of proteasome-Induced Proteolysis in skeletal muscle by B-Hydroxy-B-Methylbutyrate in cancer-induced muscle loss.Cancer Res 2005;65(1):277-283
11 HJ Smith,SM Wyke and MJ Tisdale Role of protein kinase C and NF-κB in proteolysis-inducing factor-induced proteasome expression in C2C12 myotube British Journal of Cancer (2004) 90,1850-1857
12 Lecker SH,Solomon V, Mitch WE,et al Muscle protein breakdown and the critical role of the ubiquitin-proteasome pathway in normal and disease states[J].J Nutr,1999,129(1S Suppl):227S-237S.
13 Lorite MJ,Smith HJ,Amold JA,et al Activation of ATP-ubiquitin-dependent proteolysis in skeletal muscle in vivo and murine myoblasts in vitro by a proteolysis-inducing factor(PIF)[J]. Br J Cancer,2001.85(2):297-302
14 Lorite MJ, Thompson MG, Drake JL,et al Mechanism of muscle protein degradation induced by a cancer cachectic factor[J].Br J Cancer,1998.78(7):850-856.
15 MCC Gomes-Marcondes,HJ Smith, JC Cooper and MJ Tisdale Development of an in-vitro model system to investigate the mechanism of muscle protein catabolism induced by proteolysis-inducing factor. British Journal of Cancer (2002) 86.1628-1633
16 Pawlik TM,Souba WW,Bode BP. A sparagine uptake in rat hepatocytes resolution of a paradox and insights into substrate-dependent transporter regulation[J]. Amino Acids. 2001,20(4):335-352
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18 Portor D, Weremowicz S, Chin K, Seth P, et al. (2003) A neural survival factor is a candidate oncogene in breast cancer. Proc. Nat. Acad. Sci. USA 100:10931-10936
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21 Smith HJ,Lorite MJ,Tisdale MJ. Effect of a cancer cachectic factor on protein synthesis/degradation in murine C2C12 myoblasts:modulation by eicosapentaenoic acid[J].Cancer Res,1999,59(21):5507-5513.
22 Smith HJ,Tisdale MJ. Induction of apoptosis by a cachectic-factor in Murine myotube and inhibition by eicosapentaenoic acid[J]. Apoptosis,2003,8(2):161-169.
23 Smith HJ,Greenberg NA, Tisdale MJ. Effect of eicosapentaenoic acid, protein and amino acids on protein synthesis and degradation in skeletal muscle of cachetic mice J. Cancer,2004;91(2):408-412
24 Tisdale MJ.Biochemical mechanisms J. Inhibition of tumour-induced lipolysis in vitro and cachexia and tumour growth in vivo by eicosapentaenoic acid.Curr Opin Clin Mutr Metab Care,2002;5(4):401-405
25 Todorov, P., McDevitt, T., Cariuk, P., Coles, B.,Deacon, M., and Tisdale, M. Characterization of a cancer cachectic factor. (1996) Cancer Res.56,1256-1261
26 Todorov P,Tisdale MJ(1996b) Induction of muscle protein degradation and weight loss by a tumour product. cancer Res 56:1256-1261
27 Wang Z, Corey E, Hass GM, Higano CS,et al.(2003). Expression of the human cachexia-associated protein(HCAP) in prostate cancer and in a prostate cancer animal model of cachexia. Int. J. Cancer 105:123-129
28 Watchorn TM, Waddell ID, Dowidar N, and Ross JA. Proteolysis-inducing factor regulates hepatic gene expression via transcription factors NF-kB and STAT3. FASEB J 15:562-564.2001
29 Watchorn TM, Dowidar N, Dejong CH, Waddell ID, Garden OJ, Ross JA The cachectic mediator proteolysis inducing factor activates NF-kappaB and STAT3 in human Kupffer cells and monocytes Int J Oncol.2005 Oct;27(4):1105-11
30 Whitehouse AS,Khal J, Tisdale MJ. Induction of protein catabolism in myotubes by 15(S)-hydroxyeicosatetraenoic acid through increased expression of the ubiquitin-proteasome pathway[J]. Br J Cancer,2003.89(4):737-745
31 Whitehouse AS, Tisdale MJ Increased expression of the ubiquitin-proteasome pathway in murine myotubes by proteolysis-inducing factor (PIF) is associated with activation of the transcription factor NF-kappaB Br J Cancer,2003 Sep 15;89(6):1116-22
32 Wigmore SJ, Fearon KCH, Sangster K, et al Cytokine regulation of constitutive production of interleukin-8 and -6 by human pancreatic cancer cell lines and serum cytoline concentrations in patients with pancreatic cancer. Int J Oncol 21:881-886, 2002
33 Irimura, T., Yamori, T., Bennett, S. C, Ota, D. M., and Cleary, K. R. The relationship of collagenolytic activity to stage of human colorectal carcinoma. Int. J. Cancer,40:24-31, 1987.
34 Yamori, T., Kimura. H., Stewart, K., ota, D. M. Cleary, K. R., and Irimura, T. Differential production of high molecular weight sulfate glycoproteins in normal colonie mucosa, primary colon carcinoma and metastase (1987) Cancer Res.47,2741-2747
35 Yamori, T., Ota, D. M., Cleary, K. R., Hoff. S., Hager, L. G., and Irimura, T. Monoclonal antibody against human colonie sulfomucin:immunochemical detection of its binding sites in colonie mucosa, colorectal primary carcinoma, and metastase (1989) Cancer Res. 49,887-894
13 Bossola M,Muscaritoli M,Costelli P,et al Increased muscle proteasome activity correlates with disease severity in gastric cancer patients[J]. Ann Surg,2003,237(3):384-389.
14 Cabal-Manzano R, Bhargava P. Torres-Duarte A, etal Proteolysis inducing factor is expressed in tumours of patients with gastrointestinal cancers and correlates with weight loss[J]. Br J Cancer,2001,84(12):1599-1601
15 Cariuk P,Lorite MJ, Todorov PT,et al Induction of cachexia in mice by a product isolated from the urine of cachectic cancer patients[J]. Br J Cancer,1997,76(5):606-613
1 A.Jatoi, N.Foster, B.Wieland, et al The proteolysis-inducing factor: in search of its clinical relevance in patients with metastatic gastric/esophageal cancer. Diseases of the Esophagus (2006) 19,241-247
2 Bossola M,Muscaritoli M,Costelli P,et al Increased muscle proteasome activity correlates with disease severity in gastric cancer patients[J]. Ann Surg,2003,237(3):384-389.
3 Cabal-Manzano R, Bhargava P. Torres-Duarte A, etal Proteolysis inducing factor is expressed in tumours of patients with gastrointestinal cancers and correlates with weight loss[J]. Br J Cancer,2001,84(12):1599-1601
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