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临床医学研究所

临床医学研究所
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蔡七女 副教授

蔡七女

职称： 副教授

现职： 长庚大学副教授

信箱： pink7@cgu.edu.tw

电话： 3480, 3487

学歷： 陽明大學 Ph.D.

专长领域： 基因体学、基因调控、分子病毒

研究室

肿瘤生物学研究室

博士班学生

博士班学生

博士班学生

歷年毕业生

硕士班毕业生

硕士班毕业生

博士班毕业生

博士班毕业生

研究方向

实验室研究，主要聚焦在肝癌的治病机转、及肿瘤与微环境之交互作用。

關於早期肝癌的研究， 從 2000 年我们开始追踪一小群 B 型肝癌，以 Affymetrix U133A chip 来分析早期 B 肝肿瘤检体中的基因标记，在这研究中找到了GPC3、SPP1 為獨立危險因子 (Annals of surgical oncology. 2012 Jul. 3:455-63)。後續我們又以oncoscan為平台，发现染色体的拷贝数与病人癒后及药物反应之关係 [World Journal of Gastroenterology. 2017 November. 28; 23(44): 7818-7829; Biomedical Journal. 2021 Dec;44(6 Suppl 1):S73-S83]. 而肝癌检体genomic DNA经亚硫酸盐(bisulfite)转换后，再以焦磷酸测序（pyrosequencing analysis）来分析VTRNA2-1甲基化程度，我们发现VTRNA2-1其啟动子甲基化程度与肝癌病人復发、肿瘤大小、及无病存活率高度相关 (International Journal of Surgery. 2020 Jul;79:282-289)。

而在SOX4致癌机制上，我们发现有肿瘤组织中 SOX4 过度表现之肝癌病人, 发现其肿瘤容易有血管侵犯，远端转移，及癒后差的现象(Oncogene. 2020 Jun. 39(24):4695-4710)。 接續這個研究, 我们发现SOX4与NRF2形成复合体，能直接活化磷酸丝氨酸磷酸酶（PSPH）的转录，PSPH 的活化促进了丝氨酸生合成及其下游代谢物的产生，这些代谢物对氧化磷酸化（OXPHOS）和氧化还原平衡至关重要。而抑制 SOX4 或 NRF2 会降低 PSPH 的表达，导致氧化损伤增加（以 4-羥基壬烯醛 [4-HNE] 升高為标誌），并使 HCC 细胞对索拉非尼（Sorafenib）治疗的敏感性提高。此外， PSPH 驱动的代谢物，特别是丝氨酸 (serine)，有助於 M2 型巨噬细胞的极化，进而可能促进免疫抑制性的肿瘤微环境 (Cancer gene therapy, 2025 Nov;32(11):1218-1232)。接續這個研究，我们发现 STAT6 是 SOX4 調節轉錄標的之一，同時經由共同免疫沉澱与免疫螢光實驗確認SOX4与STAT6蛋白交互作用。而染色质免疫沉淀（ChIP）实验进一步显示，SOX4 与 STAT6 会共同结合於叶酸代谢关键酶 MTHFD2 的啟动子区域，进而调控 NADH/NADPH 的生成与核苷酸的生合成。無論是敲低 SOX4 或 STAT6，或突变其在 MTHFD2 啟动子中的SOX4或是STAT6结合位点，都会导致 MTHFD2 表达下降、NADPH 含量降低以及核苷酸合成受损。来自 TCGA-LIHC 资料库及我们收集病患的转录体或蛋白体分析显示，SOX4、STAT6 与 MTHFD2 叁者之间存在高度正相关，且 MTHFD2 過度表達与整體存活率降低有關。臨床上，不論在我們的受試者或公開資料庫（如 GSE109211）中，SOX4/STAT6/MTHFD2 軸表現升高皆与對免疫療法或 TKIs 的抗药性有关。代谢组学分析也显示，SOX4/STAT6/MTHFD2 高表达的肿瘤中，NADPH 和核苷酸的合成显着增加。而在具 TKIs 抗性的病人衍生异种移植（PDx）模型中，针对 STAT6 或 MTHFD2 的抑制策略可有效抑制肿瘤生长。综合而言，我们的研究确认 SOX4–STAT6–MTHFD2 軸是推動肝癌發展与治療抗性的關鍵路徑，並為難治性肝癌提供了一個具潛力的治療靶點。此部分發表於Cell death and diseases, 2026 Jan 3;17(1):154.

整體而言，我們的研究由「分子標記鑑定」推進至「代謝驅動腫瘤進展与抗藥性機轉」之系統性解析，並建立具轉譯潛力的治療標的。未來我們的研究將透過持續深化腫瘤代謝与微環境交互作用之研究，我們期望為抗藥型肝癌提供更有效且個人化的治療方向。

近期发表论文

  1. Association Of GJB2 P.V37I With Sudden Sensorineural Hearing Loss and Endoplasmic Reticulum Stress. Lien KH, Tsai CL, Lee YS, Chen TY, Chao WC, Hu CY, Chang PH, and Tsai CN*Otolaryngology–Head and Neck Surgery, 2026 doi: 10.1002/ohn.70263

  2. Hypomethylation of VTRNA2-1 Promoter Predicts Adverse Outcomes in Peripheral Artery Disease, Clin Epigenetics. Tsai ML, Huang YC, Ho MY, Yeh JK, Chen CC, Chia CY, Fan WL, Hsieh IC, Tsai CN & Wang CY* 2026 Feb 27. doi: 10.1186/s13148-026-02087-z. Online ahead of print.

  3. Kang YC, Tseng YJ , Peng WH , Hung HC , Lin PH , Montales KP , Sherman E , Peregrin J , Wang HH, Kang C, Teng YC, Huang CY, Tsai CL , Chang YF, Chen J , Tezel G , He Y , Li TD , Stiles L, Shirihai Q, Tsang SH, Lai CC, Tsai CN*, Lin CS*, Wang NK* Disrupted Energy Metabolism is Associated with Retinal Ganglion Cell Degeneration in Autosomal Dominant Optic Atrophy, Science Advances, 2026 February, 12: eadx7815
  4. Application of CTC-Derived Spheroid for Drug Screening toward Personalized Treatment in patients with Breast Cancer. Chou HH, Che TF, Lee KJ, Chen SC, Chen JY, Huang YJ, Lim SC, Huang SC, Tsai CL, Chang YC*, Tsai CN* Translational Oncology, 2026, 63: 102573.
  5. SOX4-STAT6-MTHFD2 Axis Drives Hepatocellular Carcinoma Progression and Treatment Resistance. Tsai CL#, Yu MC#, Hsu CL, Tang HY, Lee YS, Chi LM, Lin SE, Cheng ML, Hsu HY, Tsai CN*,  Cell death and diseases, 2026, DOI:10.1038/s41419-025-08394-2
  6. NRF2-SOX4 complex regulates PSPH in hepatocellular carcinoma and modulates M2 macrophage differentiation. Tsai CN#, Yu MC#, Lee YS, Feng KC, Wu CH, Li YC, Cheng ML, Lin SE, Huang SF, Lin TA, Cheng ML, Tsai CL* Cancer gene therapy 2025 DOI: 10.1038/s41417-025-00951-3
  7. Emerging Norovirus GII.12 infection in 2010 in Northern Taiwan. Tsai CN, Chang YC, Chao HC, Hsu YH, Wang YH, Chen SY* J Formos Med Assoc. 2024 Aug 17:S0929-6646(24)00344-9.
  8. Abundance of Prevotella copri in gut microbiota is inversely related to a healthy diet in patients with type 2 diabetes. Tsai CY, Liu PY, Huang MC, Chang CI, Chen HY, Chou YH, Tsai CN*, and Lin CH*. Journal of Food and Drug Analysis, 2023, DOI:10.38212/2224-6614.3484
  9. Starvation-inactive mTOR triggers cell migration through ULK1/TKS5/MT1-MMP pathway in ovarian carcinoma. Lin CY, Wu KY, Chi LM, Tang YH, Huang HJ, Lai CH, Tsai CN* and Tsai CL*  Autophagy, 2023, Dec;19(12):3151-3168.
  10. The decline of circulating tumor cell clusters count for predicting the treatment response in breast cancer patients. Chou HH, Che TF, Chen SC, Tsai CN, Chang Y*, Chen, FM 2022 Journal of Clinical Oncology 40, no. 16_suppl (June 01, 2022) e13009-e13009.
  11. Vessels that encapsulate tumor clusters (VETC) pattern is a poor prognostic factor in patients with hepatocellular carcinoma: An analysis of microvessel density. Huang CW, L, Lin SE, Huang SF, Yu MC, Tang JH, Tsai CN and Hsu HY* Cancers (Basel). 2022 Nov 3;14(21):5428.
  12. JAK2-Mediated Phosphorylation of Stress-Induced Phosphoprotein-1 (STIP1) in Human Cells. Chao A, Liao MJ, Chen SH, Lee YS, Tsai CN, Lin CY, Tsai CL* Int J Mol Sci. 2022 Feb 22;23(5):2420. doi: 10.3390/ijms23052420.
  13. Gut microbial signatures for glycemic responses of GLP-1 receptor agonists in type 2 diabetic patients: A pilot study. Tsai CY#, Lu HC#, Chou YH, Po-Yu Liu, Chen HY, Huang MC, Lin CH*, Tsai CN*. Frontiers in Endocrinology. 2022 Jan 10;12:814770. doi: 10.3389/fendo.2021.814770. eCollection 2021.
  14. Percentage genome change and chromosome 7q amplification predict sorafenib response in advanced hepatocellular carcinoma. Yu MC, Wu TH, Lee CW, Lee YS, Lian JH, Tsai CL, Hsieh SY, Tsai CN*, Biomedical Journal, 2021 Dec;44(6 Suppl 1):S73-S83. Epub 2020 Jul 15
  15. Glucose activates lysine-specific demethylase 1 through KEAP1/p62 Pathway. Lin CY, Chang CB, Wu RC, Chao A, Lee YS, Tsai CN, Chen CH, Yen CF, Tsai CL*. Antioxidants. 2021 Nov. 26;10(12):1898
  16. Clinical and virological characteristics of viral shedding in children with norovirus gastroenteritis. Lee CC#, Chiu CH#, Lee HY#, Tsai CN, Chen CL, Chen SY*. J Microbiol Immunol Infect. 2021 Oct. 30:S1684-1182(21)00233
  17. GPR30 activation by 17β-estradiol promotes p62 phosphorylation and increases estrogen receptor α protein expression by inducing its release from a complex formed with KEAP1. Tsai CL, Lin CY, Chao A, Lee YS, Wu RC, Tsai CN, Yen CF, Chao AS*. J. Pers. Med. 2021. Sep 11;11(9):906.
  18. Clinical significance of the fucosyltransferase 2 (FUT2) secretor status in children hospitalized with acute gastroenteritis in Taiwan. Lin HY, Lai HH, Elaine Chen YF, Chao HC, Tsai CN, Chang YJ, Chen SY. J Formos Med Assoc. 2021 Jan;120(1 Pt 1):212-216.
  19. Glycogen synthase kinase-3 beta (GSK3β)-mediated phosphorylation of ETS1 promotes progression of ovarian carcinoma. Tsai CL, Jung SM, Chi LM, Tsai CN, Lin CY, Chao A, Lee YS. Aging (Albany NY). 2021 May 23;13(10):13739-13763. doi: 10.18632/aging.202966. Epub 2021 May 23.
  20. Viral shedding in gastroenteritis in children caused by variants and novel recombinant norovirus infections. Cheng HY, Lee CC, Chang YC, Tsai CN, Chao HC, Tsai YT, Hsieh CH, Su SS, Chen SY. Medicine (Baltimore). 2021 Mar 26;100(12):e25123. doi: 10.1097/MD.0000000000025123.
  21. Methylation status of vault RNA 2-1 promoter is a predictor of glycemic response to glucagon-like peptide-1 analog therapy in type 2 diabetes mellitus. Lin CH, Lee YS, Huang YY, Tsai CN*. BMJ Open Diabetes Res Care. 2021 Mar;9(1):e001416. doi: 10.1136/bmjdrc-2020-001416.
  22. SOX4 activates CXCL12 in hepatocellular carcinoma cells to modulate endothelial cell migration and angiogenesis in vivo. Tsai CN, Yu SC, Lee CW, Pang JS, Wu CH, Lin SE, Chung YH, Tsai CL, Hsieh SY, Yu MC. Oncogene. 2020 Jun;39(24):4695-4710. doi: 10.1038/s41388-020-1319-z. Epub 2020 May 13.
  23. Esculetin Ameliorates Lipopolysaccharide-Induced Acute Lung Injury in Mice Via Modulation of the AKT/ERK/NF-κB and RORγt/IL-17 Pathways. Lee HC#, Liu FC#, Tsai CN, Chou AH, Liao CC, Yu HP. Inflammation. 2020 Jun;43(3):962-974. doi: 10.1007/s10753-020-01182-4.
  24. Association of gut microbiota composition and copy number variation with Kasai procedure outcomes in infants with biliary atresia. Elaine Chen YF, Lai MW, Tsai CN, Lai JY, Yang YC, Chen SY. Pediatr Neonatol. 2020 Apr;61(2):238-240. doi: 10.1016/j.pedneo.2019.12.011. Epub 2020 Jan 7.
  25. Differential hypermethylation of the VTRNA2-1 promoter in hepatocellular carcinoma as a prognostic factor: Tumor marker prognostic study. Yu MC, Lee CW, Lin CH, Wu CH, Lee YS, Tsai CL, Tsai CN*. Int J Surg. 2020 Jul;79:282-289. doi: 10.1016/j.ijsu.2020.05.016. Epub 2020 May 14.
  26. Divergence of group a rotavirus with genetic variations before and after introduction of rotavirus vaccines in northern Taiwan. Chen YE, Lee CC, Chiu CH, Chang YC, Tsai CN, Chao HC, Kong SS, Chen SY. Medicine (Baltimore). 2020 Feb;99(9):e19253. doi: 10.1097/MD.0000000000019253.
  27. Genetic analysis of a Taiwanese family identifies a DMRT3-OAS3 interaction that is involved in human sexual differentiation through the regulation of ESR1 expression. Tsai CL, Tsai CN, Lee YS, Wang HS, Lee LY, Lin CY, Yang SY, Chao A. Fertil Steril. 2020 Jul;114(1):133-143. doi: 10.1016/j.fertnstert.2020.03.008. Epub 2020 Jun 16.