Influence of heat shock protein A2 on proliferation, migration, and invasion of pancreatic adenocarcinoma cells <i>via</i> upregulation of YAP_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

JU Tongfa ¹ , LI Weibo ² , WU Zesheng ³ ,  ZHAI Lulu ⁴

1. Department of General Surgery, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou 310006, P. R. China;
2. Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Zhongnan Hospital of Wuhan University, Wuhan 310006, P. R. China;
3. Department of Emergency Medicine, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou 310006, P. R. China;
4. Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei 230001, P. R. China;

Corresponding author：

ZHAI Lulu, Email: jackyzhai123@163.com

Keywords：

pancreatic adenocarcinoma; heat shock protein; heat shock protein A2; invasion; migration

DOI：

10.7507/1007-9424.202411062

Video：

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Objective To investigate the influencet of heat shock protein A2 (HSPA2) on the biological behavior of pancreatic adenocarcinoma cells and its mechanism. Methods The expression of HSPA2 in the human pancreatic adenocarcinoma cell lines PANC-1, BxPC-3, and AsPC-1 were determined using the Western blot analysis. The expression levels of heat shock protein A2 (HSPA2) were determined in human pancreatic cancer cell lines (PANC-1, BxPC-3, and AsPC-1) using Western blotting. Subsequently, the cells with the lowest and highest HSPA2 expression levels among these three lines were selected for conducting overexpression and knockdown experiments targeting HSPA2, respectively. The cellular proliferation, migration, and invasion capabilities were assessed using MTT, clonogenic, Transwell assays, respectively. Additionally, the impact of HSPA2 on the expression of key markers of epithelial-mesenchymal transition (EMT) was examined using the Western blot. The potential target molecules of HSPA2 were identified through immunoprecipitation assay and mass spectrometry. The rescue experiments further explored the regulatory relation between HSPA2 and its target molecules. The influence of HSPA2 on pancreatic adenocarcinoma growth was investigated through establishment of xenograft tumor model in nude mice.Results The HSPA2 exhibited the lowest expression level in the PANC-1 cells and the highest expression level in the AsPC-1 cells among the three cell lines. Subsequent functional studies demonstrated that overexpression of HSPA2 in the PANC-1 cells significantly promoted proliferation, migration, and invasion, while knockdown of HSPA2 expression in the AsPC-1 cells markedly inhibited these processes. The Western blot analysis further showed that HSPA2 overexpression upregulated E-cadherin and downregulated N-cadherin/Vimentin, whereas HSPA2 knockdown produced opposite effects. The rescue experiments indicated that HSPA2 promoted the EMT in pancreatic adenocarcinoma cells by upregulating YAP. The subcutaneous xenograft tumor experiments in the nude mice showed that HSPA2 knockdown inhibited tumour growth. Conclusion The results of this study suggest that HSPA2 promotes EMT via upregulating YAP, which facilitates proliferation, migration, and invasion of pancreatic adenocarcinoma cells.

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6.	Hu ZI, O’Reilly EM. Therapeutic developments in pancreatic cancer. Nat Rev Gastroenterol Hepatol, 2024, 21(1): 7-24.
7.	Yang S, Xiao H, Cao L. Recent advances in heat shock proteins in cancer diagnosis, prognosis, metabolism and treatment. Biomed Pharmacother, 2021, 142: 112074. doi: 10.1016/j.biopha.2021.112074.
8.	Sha G, Jiang Z, Zhang W, et al. The multifunction of HSP70 in cancer: Guardian or traitor to the survival of tumor cells and the next potential therapeutic target. Int Immunopharmacol, 2023, 122: 110492. doi: 10.1016/j.intimp.2023.110492.
9.	Elmallah MIY, Cordonnier M, Vautrot V, et al. Membrane-anchored heat-shock protein 70 (Hsp70) in cancer. Cancer Lett, 2020, 469: 134-141.
10.	Kampinga HH, Hageman J, Vos MJ, et al. Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones, 2009, 14(1): 105-111.
11.	Zhai LL, Xie Q, Zhou CH, et al. Overexpressed HSPA2 correlates with tumor angiogenesis and unfavorable prognosis in pancreatic carcinoma. Pancreatology, 2017, 17(3): 457-463.
12.	Zhai LL, Qiao PP, Sun YS, et al. Upregulated HSPA2 predicts early relapse of pancreatic cancer after surgery. Gland Surg, 2021, 10(7): 2140-2149.
13.	Zhai LL, Qiao PP, Sun YS, et al. Tumorigenic and immunological roles of Heat shock protein A2 in pancreatic cancer: a bioinformatics analysis. Rev Assoc Med Bras (1992), 2022, 68(4): 470-475.
14.	Daugaard M, Jäättelä M, Rohde M. Hsp70-2 is required for tumor cell growth and survival. Cell Cycle, 2005, 4(7): 877-880.
15.	Jagadish N, Parashar D, Gupta N, et al. Heat shock protein 70-2 (HSP70-2) is a novel therapeutic target for colorectal cancer and is associated with tumor growth. BMC Cancer, 2016, 16: 561. doi: 10.1186/s12885-016-2592-7.
16.	Jagadish N, Agarwal S, Gupta N, et al. Heat shock protein 70-2 (HSP70-2) overexpression in breast cancer. J Exp Clin Cancer Res, 2016, 35(1): 150. doi: 10.1186/s13046-016-0425-9.
17.	Garg M, Kanojia D, Saini S, et al. Germ cell-specific heat shock protein 70-2 is expressed in cervical carcinoma and is involved in the growth, migration, and invasion of cervical cells. Cancer, 2010, 116(16): 3785-3796.
18.	Kampinga HH, Hageman J, Vos MJ, et al. Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones, 2009, 14(1): 105-111.
19.	Chang WH, Ho BC, Hsiao YJ, et al. JAG1 is associated with poor survival through inducing metastasis in lung cancer. PLoS One, 2016, 11(3): e0150355. doi: 10.1371/journal.pone.0150355.
20.	Garg M, Kanojia D, Seth A, et al. Heat-shock protein 70-2 (HSP70-2) expression in bladder urothelial carcinoma is associated with tumour progression and promotes migration and invasion. Eur J Cancer, 2010, 46(1): 207-215.
21.	Singh S, Suri A. Targeting the testis-specific heat-shock protein 70-2 (HSP70-2) reduces cellular growth, migration, and invasion in renal cell carcinoma cells. Tumour Biol, 2014, 35(12): 12695-12706.
22.	Moroishi T, Hansen CG, Guan KL. The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer, 2015, 15(2): 73-79.
23.	Mao W, Mai J, Peng H, et al. YAP in pancreatic cancer: oncogenic role and therapeutic strategy. Theranostics, 2021, 11(4): 1753-1762.
24.	Franklin JM, Wu Z, Guan KL. Insights into recent findings and clinical application of YAP and TAZ in cancer. Nat Rev Cancer, 2023, 23(8): 512-525.
25.	Salcedo Allende MT, Zeron-Medina J, Hernandez J, et al. Overexpression of Yes associated protein 1, an independent prognostic marker in patients with pancreatic ductal adenocarcinoma, correlated with liver metastasis and poor prognosis. Pancreas, 2017, 46(7): 913-920.
26.	Li N, Yang G, Luo L, et al. lncRNA THAP9-AS1 promotes pancreatic ductal adenocarcinoma growth and leads to a poor clinical outcome via sponging miR-484 and interacting with YAP. Clin Cancer Res, 2020, 26(7): 1736-1748.
27.	Liu M, Zhang Y, Yang J, et al. Zinc-dependent regulation of ZEB1 and YAP1 coactivation promotes epithelial-mesenchymal transition plasticity and metastasis in pancreatic cancer. Gastroenterology, 2021, 160(5): 1771-1783.
28.	Ma H, Kong L, Liu L, et al. ENO1 contributes to the gemcitabine resistance of pancreatic cancer through the YAP1 signaling pathway. Mol Carcinog, 2024, 63(7): 1221-1234.
29.	Jiang Z, Zhou C, Cheng L, et al. Inhibiting YAP expression suppresses pancreatic cancer progression by disrupting tumor-stromal interactions. J Exp Clin Cancer Res, 2018, 37(1): 69. doi: 10.1186/s13046-018-0740-4.
30.	Park J, Eisenbarth D, Choi W, et al. YAP and AP-1 cooperate to initiate pancreatic cancer development from ductal cells in mice. Cancer Res, 2020, 80(21): 4768-4779.
31.	Gruber R, Panayiotou R, Nye E, et al. YAP1 and TAZ control pancreatic cancer initiation in mice by direct up-regulation of JAK-STAT3 signaling. Gastroenterology, 2016, 151(3): 526-539.
32.	Liu Z, Hayashi H, Matsumura K, et al. Hyperglycaemia induces metabolic reprogramming into a glycolytic phenotype and promotes epithelial-mesenchymal transitions via YAP/TAZ-Hedgehog signalling axis in pancreatic cancer. Br J Cancer, 2023, 128(5): 844-856.

1. Park W, Chawla A, O’Reilly EM. Pancreatic cancer: A review. JAMA, 2021, 326(9): 851-862.
2. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin, 2024, 74(1): 12-49.
3. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024, 74(3): 229-263.
4. Wood LD, Canto MI, Jaffee EM, et al. Pancreatic cancer: Pathogenesis, screening, diagnosis, and treatment. Gastroenterology, 2022, 163(2): 386-402.
5. Halbrook CJ, Lyssiotis CA, Pasca di Magliano M, et al. Pancreatic cancer: Advances and challenges. Cell, 2023, 186(8): 1729-1754.
6. Hu ZI, O’Reilly EM. Therapeutic developments in pancreatic cancer. Nat Rev Gastroenterol Hepatol, 2024, 21(1): 7-24.
7. Yang S, Xiao H, Cao L. Recent advances in heat shock proteins in cancer diagnosis, prognosis, metabolism and treatment. Biomed Pharmacother, 2021, 142: 112074. doi: 10.1016/j.biopha.2021.112074.
8. Sha G, Jiang Z, Zhang W, et al. The multifunction of HSP70 in cancer: Guardian or traitor to the survival of tumor cells and the next potential therapeutic target. Int Immunopharmacol, 2023, 122: 110492. doi: 10.1016/j.intimp.2023.110492.
9. Elmallah MIY, Cordonnier M, Vautrot V, et al. Membrane-anchored heat-shock protein 70 (Hsp70) in cancer. Cancer Lett, 2020, 469: 134-141.
10. Kampinga HH, Hageman J, Vos MJ, et al. Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones, 2009, 14(1): 105-111.
11. Zhai LL, Xie Q, Zhou CH, et al. Overexpressed HSPA2 correlates with tumor angiogenesis and unfavorable prognosis in pancreatic carcinoma. Pancreatology, 2017, 17(3): 457-463.
12. Zhai LL, Qiao PP, Sun YS, et al. Upregulated HSPA2 predicts early relapse of pancreatic cancer after surgery. Gland Surg, 2021, 10(7): 2140-2149.
13. Zhai LL, Qiao PP, Sun YS, et al. Tumorigenic and immunological roles of Heat shock protein A2 in pancreatic cancer: a bioinformatics analysis. Rev Assoc Med Bras (1992), 2022, 68(4): 470-475.
14. Daugaard M, Jäättelä M, Rohde M. Hsp70-2 is required for tumor cell growth and survival. Cell Cycle, 2005, 4(7): 877-880.
15. Jagadish N, Parashar D, Gupta N, et al. Heat shock protein 70-2 (HSP70-2) is a novel therapeutic target for colorectal cancer and is associated with tumor growth. BMC Cancer, 2016, 16: 561. doi: 10.1186/s12885-016-2592-7.
16. Jagadish N, Agarwal S, Gupta N, et al. Heat shock protein 70-2 (HSP70-2) overexpression in breast cancer. J Exp Clin Cancer Res, 2016, 35(1): 150. doi: 10.1186/s13046-016-0425-9.
17. Garg M, Kanojia D, Saini S, et al. Germ cell-specific heat shock protein 70-2 is expressed in cervical carcinoma and is involved in the growth, migration, and invasion of cervical cells. Cancer, 2010, 116(16): 3785-3796.
18. Kampinga HH, Hageman J, Vos MJ, et al. Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones, 2009, 14(1): 105-111.
19. Chang WH, Ho BC, Hsiao YJ, et al. JAG1 is associated with poor survival through inducing metastasis in lung cancer. PLoS One, 2016, 11(3): e0150355. doi: 10.1371/journal.pone.0150355.
20. Garg M, Kanojia D, Seth A, et al. Heat-shock protein 70-2 (HSP70-2) expression in bladder urothelial carcinoma is associated with tumour progression and promotes migration and invasion. Eur J Cancer, 2010, 46(1): 207-215.
21. Singh S, Suri A. Targeting the testis-specific heat-shock protein 70-2 (HSP70-2) reduces cellular growth, migration, and invasion in renal cell carcinoma cells. Tumour Biol, 2014, 35(12): 12695-12706.
22. Moroishi T, Hansen CG, Guan KL. The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer, 2015, 15(2): 73-79.
23. Mao W, Mai J, Peng H, et al. YAP in pancreatic cancer: oncogenic role and therapeutic strategy. Theranostics, 2021, 11(4): 1753-1762.
24. Franklin JM, Wu Z, Guan KL. Insights into recent findings and clinical application of YAP and TAZ in cancer. Nat Rev Cancer, 2023, 23(8): 512-525.
25. Salcedo Allende MT, Zeron-Medina J, Hernandez J, et al. Overexpression of Yes associated protein 1, an independent prognostic marker in patients with pancreatic ductal adenocarcinoma, correlated with liver metastasis and poor prognosis. Pancreas, 2017, 46(7): 913-920.
26. Li N, Yang G, Luo L, et al. lncRNA THAP9-AS1 promotes pancreatic ductal adenocarcinoma growth and leads to a poor clinical outcome via sponging miR-484 and interacting with YAP. Clin Cancer Res, 2020, 26(7): 1736-1748.
27. Liu M, Zhang Y, Yang J, et al. Zinc-dependent regulation of ZEB1 and YAP1 coactivation promotes epithelial-mesenchymal transition plasticity and metastasis in pancreatic cancer. Gastroenterology, 2021, 160(5): 1771-1783.
28. Ma H, Kong L, Liu L, et al. ENO1 contributes to the gemcitabine resistance of pancreatic cancer through the YAP1 signaling pathway. Mol Carcinog, 2024, 63(7): 1221-1234.
29. Jiang Z, Zhou C, Cheng L, et al. Inhibiting YAP expression suppresses pancreatic cancer progression by disrupting tumor-stromal interactions. J Exp Clin Cancer Res, 2018, 37(1): 69. doi: 10.1186/s13046-018-0740-4.
30. Park J, Eisenbarth D, Choi W, et al. YAP and AP-1 cooperate to initiate pancreatic cancer development from ductal cells in mice. Cancer Res, 2020, 80(21): 4768-4779.
31. Gruber R, Panayiotou R, Nye E, et al. YAP1 and TAZ control pancreatic cancer initiation in mice by direct up-regulation of JAK-STAT3 signaling. Gastroenterology, 2016, 151(3): 526-539.
32. Liu Z, Hayashi H, Matsumura K, et al. Hyperglycaemia induces metabolic reprogramming into a glycolytic phenotype and promotes epithelial-mesenchymal transitions via YAP/TAZ-Hedgehog signalling axis in pancreatic cancer. Br J Cancer, 2023, 128(5): 844-856.

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