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臨床醫學研究所

臨床醫學研究所
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蔡七女 副教授

蔡七女

職稱： 副教授

現職： 長庚大學副教授

信箱： pink7@cgu.edu.tw

電話： 3480, 3487

學歷： 陽明大學 Ph.D.

專長領域： 基因體學、基因調控、分子病毒

研究室

腫瘤生物學研究室

博士班學生

博士班學生

博士班學生

歷年畢業生

碩士班畢業生

碩士班畢業生

博士班畢業生

博士班畢業生

研究方向

實驗室研究，主要聚焦在肝癌的治病機轉、及腫瘤與微環境之交互作用。

關於早期肝癌的研究， 從 2000 年我們開始追蹤一小群 B 型肝癌，以 Affymetrix U133A chip 來分析早期 B 肝腫瘤檢體中的基因標記，在這研究中找到了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，發現染色體的拷貝數與病人癒後及藥物反應之關係 [World Journal of Gastroenterology. 2017 November. 28; 23(44): 7818-7829; Biomedical Journal. 2021 Dec;44(6 Suppl 1):S73-S83]. 而肝癌檢體genomic DNA經亞硫酸鹽(bisulfite)轉換後，再以焦磷酸测序（pyrosequencing analysis）來分析VTRNA2-1甲基化程度，我們發現VTRNA2-1其啟動子甲基化程度與肝癌病人復發、腫瘤大小、及無病存活率高度相關 (International Journal of Surgery. 2020 Jul;79:282-289)。

而在SOX4致癌機制上，我們發現有腫瘤組織中 SOX4 過度表現之肝癌病人, 發現其腫瘤容易有血管侵犯，遠端轉移，及癒後差的現象(Oncogene. 2020 Jun. 39(24):4695-4710)。 接續這個研究, 我們發現SOX4與NRF2形成複合體，能直接活化磷酸絲氨酸磷酸酶（PSPH）的轉錄，PSPH 的活化促進了絲氨酸生合成及其下游代謝物的產生，這些代謝物對氧化磷酸化（OXPHOS）和氧化還原平衡至關重要。而抑制 SOX4 或 NRF2 會降低 PSPH 的表達，導致氧化損傷增加（以 4-羥基壬烯醛 [4-HNE] 升高為標誌），並使 HCC 細胞對索拉非尼（Sorafenib）治療的敏感性提高。此外， PSPH 驅動的代謝物，特別是絲氨酸 (serine)，有助於 M2 型巨噬細胞的極化，進而可能促進免疫抑制性的腫瘤微環境 (Cancer gene therapy, 2025 Nov;32(11):1218-1232)。接續這個研究，我們發現 STAT6 是 SOX4 調節轉錄標的之一，同時經由共同免疫沉澱與免疫螢光實驗確認SOX4與STAT6蛋白交互作用。而染色質免疫沉澱（ChIP）實驗進一步顯示，SOX4 與 STAT6 會共同結合於葉酸代謝關鍵酶 MTHFD2 的啟動子區域，進而調控 NADH/NADPH 的生成與核苷酸的生合成。無論是敲低 SOX4 或 STAT6，或突變其在 MTHFD2 啟動子中的SOX4或是STAT6結合位點，都會導致 MTHFD2 表達下降、NADPH 含量降低以及核苷酸合成受損。來自 TCGA-LIHC 資料庫及我們收集病患的轉錄體或蛋白體分析顯示，SOX4、STAT6 與 MTHFD2 三者之間存在高度正相關，且 MTHFD2 過度表達與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 軸表現升高皆與對免疫療法或 TKIs 的抗藥性有關。代謝組學分析也顯示，SOX4/STAT6/MTHFD2 高表達的腫瘤中，NADPH 和核苷酸的合成顯著增加。而在具 TKIs 抗性的病人衍生異種移植（PDx）模型中，針對 STAT6 或 MTHFD2 的抑制策略可有效抑制腫瘤生長。綜合而言，我們的研究確認 SOX4–STAT6–MTHFD2 軸是推動肝癌發展與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「代謝驅動腫瘤進展與抗藥性機轉」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與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。

近期發表論文

  1. 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
  2. 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.
  3. 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
  4. 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
  5. 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.
  6. 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
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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
  13. 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
  14. 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
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. 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.
  25. 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.