Correlation between Clinicopathology and Expression of HSP70, BAG1 and Raf-1 in Human Diffuse Type Gastric Carcinoma

미만형 위암에서 임상병리학적 인자와 Hsp70, BAG1과 Raf-1 발현간의 상관성

Jung, Sang Bong;Lee, Hyoun Wook;Chung, Kyung Tae

  • Received : 2015.12.08
  • Accepted : 2016.01.25
  • Published : 2016.01.30


The aim of this study was to evaluate the relationships between the expression of Heat shock protein70 (HSP70), Raf-1 and Bcl-2-associated athanogene-1 (BAG1) protein in diffuse type gastric carcinoma and examine association of HSP70, Raf-1 and BAG1 expression with various clinic-pathological factors and survival. Heat shock protein70 is induced in the cells in response to various stress conditions, including carcinogens. Overexpression of heat shock protein 70 has been observed in many types of cancer. The proto-oncoprotein Raf is pivotal for mitogen-activated protein kinase (MAPK) signaling, and its aberrant activation has been implicated in multiple human cancers. Overexpression of BAG1 protein has been documented in some type of human cancer. BAG1 has been reported to interact with protein involved with a variety of signal pathway, and regulation of cell differentiation, survival and apoptosis. These interaction partners include HSP70 and Raf-1. The percentage of tumors exhibiting HSP70 positivity was significantly in cases of positive lymph node metastasis (64.9%) compared to cases without lymph node metastasis (35.1%, p=0.007). HS70 expression was correlated with pathological N-stage (p=0.006). Expression of BAG1 was detected in the majority of diffuse type gastric carcinoma tissues (71.7%), especially in younger patients (80% vs 52.6%, p=0.035). Furthermore BAG1 expression was correlated with tumor size (p=0.020). Raf-1 expression was found to be significantly associated with tumor size (p=0.005). The result indicate that HSP70 was significantly correlated the progression of diffuse type gastric cancer. Expression of BAG1 and Raf-1 may be used as diagnostic markers for gastric carcinoma.


Bag1;gastric cancer;hsp70;Immunohistochemistry;raf-1


  1. David, H., Berger, L, A., Jardines, H, C. and Bruce, R. 1997. Activation of Raf-1 in human pancreatic adenocarcinoma. J. Surg. Res. 69, 199-204.
  2. Choi, H, G., Kim, J, S., Kim, K, H., Kim, K, H., Sung, M, W., Choe, J, Y., Kim, J, E. and Jung, Y, H. 2000. Expression of hypoxic signaling markers in head and neck squamous cell carcinoma and its clinical significance. Oncology 58, 144-151.
  3. Chen, L., Shi, Y, C., Jiang, C, Y., Wei, L, X., Wang, Y, L. and Dai, G, H. 2011. Expression and prognostic role of pan-Ras, Raf-1, pMEK1 and pERK1/2 in patients with hepatocellular carcinoma. Eur. J. surg. Oncol. 37, 513-520.
  4. Fiona, M., Peter, M., Kenneth, G. M., Jane, M. S., Brett, P. M., David, A, C., John, F, S. and Simon, P. L. 2006. Raf-1 is the predominant Raf isoform that mediates growth factor-stimulated growth in ovarian cancer cells. Carcinogenesis 27, 729-739.
  5. Garrido, C., Brunet, M., Didelot, C., Zermati, Y., Schmitt, E. and Kroemer, G. 2006. Heat shock proteins 27 and 70: anti-apoptotic proteins with tumorigenic properties. Cell. Cycle. 5, 2592-2601.
  6. Garrido, C., Gurbusani, S., Ravagnan, L. and Kroemer, G. 2001. Heat shock proteins: endogenous modulators of apoptotic cell death. Bio. Chem. Biophys. Res. Commun. 286, 433-442.
  7. Hilger, R, A., Scheulen, M, E. and Strumberg, D. 2002. The Ras Raf-MEK-ERK pathway in the treatment of cancer. Oncologie 25, 511-518.
  8. Antonioli, D. A. 1990. Gastric carcinoma and its precursors. Monogr. Pathol. 31, 144-180.
  9. Kitamura, K., Yamaguchi, T., Tanighchi, H., Hagiwara, A., Yamane, T. and Sawai, K. 1996. Clinicopathological characteristics of gastric cancer in the elderly. Br. J. Cancer 73, 798-802,
  10. Joly, A, L., Wettstein, G., Mignot, G., Ghiringhelli, F. and Garrido, C. 2010. Dual role of heat shock proteins as regulators of apoptosis and innate immunity. J. Innate. Immun. 2, 238-247.
  11. Kang, Y., Jung, W, Y., Lee, H., Jung, W., Lee, E., Shin, B, K., Kim, A., Kim, H, K. and Kim, B, H. 2013. Prognostic significance of heat shock protein 70 expression in early gastric carcinoma. Kor. J. Pathol. 3, 219-226.
  12. Kaur, J., Srivastava, A. and Ralhan, R. 1998. Expression of 70-kDa heat shock protein in oral lesions: Marker of biological stress or pathogenicity. Oral. Oncol. 34, 496-501.
  13. Lauren, P. 1965. The two histological main types of gastric carcinoma: diffuseand so-called intestinal-type carcinoma. an attempt at a histo-clinicalclassification. Acta. Pathol. Microbiol. Scand. 64, 31-49.
  14. Lee, J, S., Bae, S, H. and Kim, J, R. 1998. Heat-shock protein 70 and p53 protein expression in gastric carcinomas. Kor. Surg. Soc. 54, 192-200
  15. Ishigami, S., Natsugoe, S., Sanihara, T., Hokita, S., Tokushige, M., Watanabe, T., Iwaschige, H. and AIkou, T. 1997. Clinical and pathologic features of early gastric cancer in elderly patients. Hepatogastroenterology 44, 1164-1168.
  16. Canoz, O., Belenli, O. and Patiroglu, T, E. 2002. General features of gastric carcinomas and comparison of HSP70 and NK cell immunoreactivity with prognostic factors. Pathol. Oncol. Res. 8, 262-269.
  17. Jemal, A., Bray, F., Center, M. M., Ferlay, J., Ward, E. and Forman, D. 2011. Global cancer statistics. CA. Cancer J. Clin. 61, 69-90.
  18. National Cancer Information Center. Cancer Statistics in Korea.
  19. McCubrey, J. A., Steelman, L. S., Chappell, W. H., Abrams, S. L., Wong, E. W., Chang, F., Lehmann, B., Terrian, D. M., Milella, M., Tafuri, A., Stivala, F., Libra, M., Basecke, J., Evangelisti, C., Martelli, A, M. and Franklin, R. A. 2007. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim. Biophys. Acta1. 773, 1263-1284
  20. Morrison, D, K. and Cutler, R, E. 1997. The complexity of Raf-1regulation. Curr. Opin. Cell. Bio. 19,174-179.
  21. Naishiro, Y., Adachi, M., Okuda, H., Yawata, A., Mitaka, T., Takayama, S., Reed, J, C., Hinoda, Y. and Imai, K. 1999. BAG1 accelerates cell motility of human gastric cancer cells. Oncogene 18, 3244-3251.
  22. Nollen, E. A., Kabakov, A. E., Brunsting J. F., Kanon, B., Hohfeld, J. and Kampinga, H. H. 2001. Modulation of in Vivo HSP70 Chaperone activity by Hip and Bag-1. J. Biol. Chem. 276, 4677-4682.
  23. Park, T, S., Kim, H, R., Koh, J, S., Jang, S, H., Hwang, Y, I., Yoon, H, I., Chung, J, H., Kim, C, H., Kim, S, S., Kim, W, S., Jo, J., Lee, J, C. and Choi, C, M. 2014. Heat shock protein 70 as a predictive marker for platinum-based adjuvant chemotherapy in patients with resected non-small cell lung cancer. Lung. Cancer 86, 262-267.
  24. Qiu, Z., Sun, W., Zhou, C. and Zhang, J. 2015. HER2 expression variability between primary gastric cancers and corresponding lymph node metastases. Hepatogastroenterology 137, 231-233
  25. Isomoto, H., Oka, M., Yano, Y., Kanazawa, Y., Soda, H., Terada, R., Yasutake, T., Nakayama, T., Shikuwa, S., Takeshima, F., Udono, H., Murata, I., Ohtsuka, K. and Kohno, S. 2003. Expression of heat shock protein (Hsp) 70 and Hsp 40 in gastric cancer. Cancer Lett. 198, 219-228.
  26. Takayama, S., Bimston, D, N., Matzuzawa, S., Freeman, B, C., Aime, S, C., Xie, Z., Morimoto, R, I. and Reed, J, C. 1997. BAG1 modulates the chaperone activity of Hsp70/Hsc70. EMBO J. 16, 4887-4896.
  27. Saricanbaz, I., Karahacioglu, E., Ekinci, O., Bora, H., Kilic, D. and Akmansu, M. 2014. Prognostic significance of expression of CD133 and Ki-67 in gastric cancer. Asian Pac. J. Cancer Prev. 19, 8215-8219
  28. Song, J., Takeda, M. and Morimoto, R. I. 2001. Bag1-Hsp70 mediates a physiological stress signling pathway that regulates Raf-1/ERK and cell growth. Nat. Cell. Biol. 3, 276-282.
  29. Syrigos, K, N., Harrington, K, J., Karayiannakis, A, J., Sekara, E., Chatziyianni, E., Syrigou, E, I. and Waxman, J. 2003. Clinical significance of heat shock protein-70 expression in bladder cancer. Urology 61, 677-680.
  30. Takayama, S., Takaaki, S., Krajewski, S., Irie, S., Millan, J, A. and Reed J, C. 1995. Cloning and functional analysis of BAG-1: a novel Bcl-2 binding protein with anti-cell death activity. Cell 80, 279-284.
  31. Tang, S, C., Shaheta, N., Chernenko, G., Khalifa, M. and Wang, X. 1999. Expression of BAG-1 in invasive breast carcinomas. J. Clin. Oncol. 17, 1710-1719.
  32. Turner, B. C., Krajewski, S., Krajewska, M., Takayama, S., Gumbs, A. A., Rebbeck, T. R., Carter, D., Haffty, B. G. and Reed, J. C. 2001. BAG-1: a novel biomarker predicting long term survival in early-stage breast cancer. J. Clin. Oncol. 19, 992-1000.
  33. Maehara, Y, 1., Oki, E., Abe, T., Tokunaga, E., Shibahara, K., Kakeji, Y. and Sugimachi, K. 2015. Overexpression of the heat shock protein HSP70 family and p53 protein and prognosis for patients with gastric cancer. Eur. Arch. Otorhinol. 272, 219-228.
  34. Yu, X, B., Ji, L., Jian, F, L. and Hong, S. 2007. Clinicopathologic significance of BAG1 and TIMP3 expression in colon carcinoma. World J. Gastro. 28, 3883-3885.
  35. Xue, F, L., Ming, W, C., Lei, X., Lei, D., Guang, Y, M. and Man, H, L. 2012. Combined analysis of mRNA expression of ERCC1, BAG1, BRCA1, RRM1 and TUBB3 to predict prognosis in patients with non-small cell lung cancer who received adjuvant chemotherapy. J. Exp. Clin. Canc. Res. 31, 25-35.
  36. Yamauchi, H., Adachi, M., Sakata, K. I., Hareyama, M., Satoh, M., Himi, T., Takayama, S., Reed, J. C. and Imai, K. 2001. Nuclear BAG-1 localization and the risk of recurrence after radiation therapy in laryngeal carcinoma. Cancer Lett. 165, 103-110.
  37. Yawata, A., Adachi, M., Okuda, H., Naishiro, Y., Takamura, T., Hareyama, M.,Takayama, S., Reed, J. C. and Imai, K. 1998. Prolonged cell survival enhances peritoneal dissemination of gastric cancer cells. Oncogene 16, 2681-2686.
  38. Rorke, S., Murphy, S., Kalifa, M. and Tang, S, C. 2001. Prognostic significance of BAG-1 expression in non-small cell lung cancer. Int. J. Cancer 95, 317-322<317::AID-IJC1055>3.0.CO;2-J
  39. Xiaoling, W., Hong, Z., Junyi, Y., Mengyuan, K., Fatao, L., Ting, W., Jiaying, D., Yanfang, T., Lin, H. and Yun, L. 2015. Hypermethylated epidermal growth factor receptor (EGFR) promoter is associated with gastric cancer. Sci. Rep. 5, 10154