頭頸癌是世界第六常見的癌症，頭頸癌包含唇、腮腺、鼻腔、副鼻竇、咽、喉或口腔，順鉑是一種有名的癌症化療藥物，他被用在治療人類許多癌症包含頭頸癌、卵巢癌和肺癌，順鉑是由鉑金屬離子連接四個配體構成，順鉑金屬離子會和DNA的鹼基產生鍵結進而干擾DNA的複製，順鉑也會產生大量的自由基進而造成DNA的損傷，DNA的損傷會造成癌細胞凋亡，雖然順鉑是一個很強力的癌症治療策略，但是癌症會有抗藥還有轉移的問題待解決，我們之前的研究顯示PTX3表現在多種頭頸癌細胞株中會促進癌細胞轉移，順鉑在頭頸癌細胞中會產生自由基，在這次研究中我們想要釐清PTX3在順鉑處理下存活的頭頸癌細胞是否扮演抗藥性或是轉移的角色，首先我們發現自由基會透過Akt和NF-κB路徑誘導PTX3的表現，NAC會顯著的抑制自由基誘導的PTX3表現，自由基也會活化PTX3的轉錄子，然後我們發現順鉑在頭頸癌細胞中會誘導PTX3的表現，NAC會顯著的抑制順鉑誘導的PTX3表現，我們的數據顯示順鉑誘導PTX3中自由基的重要性，並且確認處理順鉑後存活的癌細胞更容易受到表皮生長因子的刺激。

Head and neck squamous cell carcinoma (HNSCC) is sixth common cancer in the world. HNSCC develops from many tissues including lip, parotid glands, nasal cavity, paranasal sinuses, pharynx, larynx or oral cavity. Cisplatin is a well-known chemotherapeutic drug. It has been used for treatment of many human cancers including head and neck, ovarian and lung cancers. Cisplatin is composed of platinum ion surrounded by four ligands. Platinum ion can form the bond of DNA bases to interfere with DNA replication mechanisms. It also induces reactive oxygen species that causes DNA damage. The DNA damage causes apoptosis of cancer cells. Although cisplatin is a strong strategy of cancer therapy, the problem of anti-cancer drug resistant and metastasis are needed to be solved. Our previous data revealed that PTX3 expression triggered metastasis in various HNSCC cell lines. Cisplatin produced ROS in HNSCC. In this study, we want to clarify whether PTX3 regulated the drug resistance and metastasis in the survival cells of HNSCC under treatments of cisplatin. First, we found that ROS induced PTX3 expression through Akt and NF-κB pathways. NAC significantly inhibited ROS-induced PTX3 expression. ROS also regulated PTX3 promoter activity. In addition, we found that cisplatin induced PTX3 expression in HNSCC cells. NAC significantly inhibited cisplatin-induced PTX3 expression. Our data suggest that the ROS is essential for cisplatin-induced PTX3 expression and the survival cancer cells after cisplatin treatment are more sensitive to epidermal growth factor stimulation.

1. Economopoulou, P., et al., The emerging role of immunotherapy in head and neck squamous cell carcinoma (HNSCC): anti-tumor immunity and clinical applications. Ann Transl Med, 2016. 4(9): p. 173.
2. Liu, X., et al., The etiologic spectrum of head and neck squamous cell carcinoma in young patients. Oncotarget, 2016. 7(40): p. 66226-66238.
3. Leemans, C.R., B.J. Braakhuis, and R.H. Brakenhoff, The molecular biology of head and neck cancer. Nat Rev Cancer, 2011. 11(1): p. 9-22.
4. Lim, H.J., et al., Targeting the PI3K/PTEN/AKT/mTOR Pathway in Treatment of Sarcoma Cell Lines. Anticancer Res, 2016. 36(11): p. 5765-5771.
5. Chang, W.C., et al., PTX3 gene activation in EGF-induced head and neck cancer cell metastasis. Oncotarget, 2015. 6(10): p. 7741-57.
6. Chan, S.H., et al., Oleate-induced PTX3 promotes head and neck squamous cell carcinoma metastasis through the up-regulation of vimentin. Oncotarget, 2017. 8(25): p. 41364-41378.
7. Magrini, E., A. Mantovani, and C. Garlanda, The Dual Complexity of PTX3 in Health and Disease: A Balancing Act? Trends Mol Med, 2016. 22(6): p. 497-510.
8. Uusitalo-Seppala, R., et al., Pentraxin 3 (PTX3) is associated with severe sepsis and fatal disease in emergency room patients with suspected infection: a prospective cohort study. PLoS One, 2013. 8(1): p. e53661.
9. Du Clos, T.W., Pentraxins: structure, function, and role in inflammation. ISRN Inflamm, 2013. 2013: p. 379040.
10. Cieslik, P. and A. Hrycek, Long pentraxin 3 (PTX3) in the light of its structure, mechanism of action and clinical implications. Autoimmunity, 2012. 45(2): p. 119-28.
11. Altmeyer, A., et al., Promoter structure and transcriptional activation of the murine TSG-14 gene encoding a tumor necrosis factor/interleukin-1-inducible pentraxin protein. J Biol Chem, 1995. 270(43): p. 25584-90.
12. Koh, S.H., et al., Long pentraxin PTX3 mediates acute inflammatory responses against pneumococcal infection. Biochem Biophys Res Commun, 2017. 493(1): p. 671-676.
13. Shiraki, A., et al., Pentraxin-3 regulates the inflammatory activity of macrophages. Biochem Biophys Rep, 2016. 5: p. 290-295.
14. Mantovani, A., et al., Pentraxins in innate immunity: from C-reactive protein to the long pentraxin PTX3. J Clin Immunol, 2008. 28(1): p. 1-13.
15. Jaillon, S., et al., The humoral pattern recognition molecule PTX3 is a key component of innate immunity against urinary tract infection. Immunity, 2014. 40(4): p. 621-32.
16. Scimeca, M., et al., Impairment of PTX3 expression in osteoblasts: a key element for osteoporosis. Cell Death Dis, 2017. 8(10): p. e3125.
17. Grcevic, D., et al., The Long Pentraxin 3 Plays a Role in Bone Turnover and Repair. Front Immunol, 2018. 9: p. 417.
18. Chi, J.Y., et al., Targeting chemotherapy-induced PTX3 in tumor stroma to prevent the progression of drug-resistant cancers. Oncotarget, 2015. 6(27): p. 23987-4001.
19. Ying, T.H., et al., Knockdown of Pentraxin 3 suppresses tumorigenicity and metastasis of human cervical cancer cells. Sci Rep, 2016. 6: p. 29385.
20. Infante, M., et al., Prognostic and diagnostic potential of local and circulating levels of pentraxin 3 in lung cancer patients. Int J Cancer, 2016. 138(4): p. 983-91.
21. Zhang, D., et al., Clinical significance and prognostic value of pentraxin-3 as serologic biomarker for lung cancer. Asian Pac J Cancer Prev, 2013. 14(7): p. 4215-21.
22. Liu, C., Y. Yao, and W. Wang, Pentraxin-3 as a prognostic marker in patients with small-cell lung cancer. Med Oncol, 2014. 31(10): p. 207.
23. Choi, B., et al., Elevated Pentraxin 3 in bone metastatic breast cancer is correlated with osteolytic function. Oncotarget, 2014. 5(2): p. 481-92.
24. Stallone, G., et al., Pentraxin 3: a novel biomarker for predicting progression from prostatic inflammation to prostate cancer. Cancer Res, 2014. 74(16): p. 4230-8.
25. Carmo, R.F., et al., Genetic variation in PTX3 and plasma levels associated with hepatocellular carcinoma in patients with HCV. J Viral Hepat, 2016. 23(2): p. 116-22.
26. Choi, B., et al., Upregulation of brain-derived neurotrophic factor in advanced gastric cancer contributes to bone metastatic osteolysis by inducing long pentraxin 3. Oncotarget, 2016. 7(34): p. 55506-55517.
27. Kondo, S., et al., Clinical impact of pentraxin family expression on prognosis of pancreatic carcinoma. Br J Cancer, 2013. 109(3): p. 739-46.
28. Zhang, J., T.Y. Wang, and X.C. Niu, Increased Plasma Levels of Pentraxin 3 Are Associated with Poor Prognosis of Colorectal Carcinoma Patients. Tohoku J Exp Med, 2016. 240(1): p. 39-46.
29. Tafani, M., et al., Up-regulation of pro-inflammatory genes as adaptation to hypoxia in MCF-7 cells and in human mammary invasive carcinoma microenvironment. Cancer Sci, 2010. 101(4): p. 1014-23.
30. Ray, P.D., B.W. Huang, and Y. Tsuji, Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal, 2012. 24(5): p. 981-90.
31. Son, Y., et al., Mitogen-Activated Protein Kinases and Reactive Oxygen Species: How Can ROS Activate MAPK Pathways? J Signal Transduct, 2011. 2011: p. 792639.
32. Reuter, S., et al., Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med, 2010. 49(11): p. 1603-16.
33. Prasad, S., S.C. Gupta, and A.K. Tyagi, Reactive oxygen species (ROS) and cancer: Role of antioxidative nutraceuticals. Cancer Lett, 2017. 387: p. 95-105.
34. Dayem, A.A., et al., Role of oxidative stress in stem, cancer, and cancer stem cells. Cancers (Basel), 2010. 2(2): p. 859-84.
35. Morgan, M.J. and Z.G. Liu, Crosstalk of reactive oxygen species and NF-kappaB signaling. Cell Res, 2011. 21(1): p. 103-15.
36. Kumari, S., et al., Reactive Oxygen Species: A Key Constituent in Cancer Survival. Biomark Insights, 2018. 13: p. 1177271918755391.
37. Hsieh, C.L., et al., Reactive oxygen species-mediated switching expression of MMP-3 in stromal fibroblasts and cancer cells during prostate cancer progression. Sci Rep, 2017. 7(1): p. 9065.
38. Radisky, D.C., et al., Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature, 2005. 436(7047): p. 123-7.
39. Nishikawa, M., Reactive oxygen species in tumor metastasis. Cancer Lett, 2008. 266(1): p. 53-9.
40. Galluzzi, L., et al., Molecular mechanisms of cisplatin resistance. Oncogene, 2012. 31(15): p. 1869-83.
41. Pendleton, K.P. and J.R. Grandis, Cisplatin-Based Chemotherapy Options for Recurrent and/or Metastatic Squamous Cell Cancer of the Head and Neck. Clin Med Insights Ther, 2013. 2013(5).
42. Zimmermann, M., et al., The epidermal growth factor receptor (EGFR) in head and neck cancer: its role and treatment implications. Radiat Oncol, 2006. 1: p. 11.
43. Hutchinson, L., Drug therapy: Cetuximab or cisplatin in HNSCC? Nat Rev Clin Oncol, 2016. 13(2): p. 66.
44. Housman, G., et al., Drug resistance in cancer: an overview. Cancers (Basel), 2014. 6(3): p. 1769-92.
45. Li, J., et al., Metformin Protects Against Cisplatin-Induced Tubular Cell Apoptosis and Acute Kidney Injury via AMPKalpha-regulated Autophagy Induction. Sci Rep, 2016. 6: p. 23975.
46. Dasari, S. and P.B. Tchounwou, Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol, 2014. 740: p. 364-78.
47. Wangpaichitr, M., et al., Relationship of Metabolic Alterations and PD-L1 Expression in Cisplatin Resistant Lung Cancer. Cell Dev Biol, 2017. 6(2).
48. Sheth, S., et al., Mechanisms of Cisplatin-Induced Ototoxicity and Otoprotection. Front Cell Neurosci, 2017. 11: p. 338.
49. Hughes, R., et al., Perivascular M2 Macrophages Stimulate Tumor Relapse after Chemotherapy. Cancer Res, 2015. 75(17): p. 3479-91.
50. Roodhart, J.M., et al., Notch1 regulates angio-supportive bone marrow-derived cells in mice: relevance to chemoresistance. Blood, 2013. 122(1): p. 143-53.