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研究生： 劉俊宏
Liu, Chun-Hung
論文名稱： 中間普雷沃菌透過interpain A- PAR-2訊號傳導與細胞衰老相關效應促進大腸癌的化療抗性
Prevotella intermedia promotes chemoresistance in colorectal cancer via interpain A-PAR-2 signaling and senescence-associated effects
指導教授： 陳振暐
Chen, Jenn-Wei
學位類別： 碩士
Master
系所名稱： 醫學院 - 微生物及免疫學研究所
Department of Microbiology & Immunology
論文出版年： 2025
畢業學年度： 113
語文別： 英文
論文頁數： 104
中文關鍵詞： 中間普雷沃菌 、結腸直腸癌 、化療抗藥性 、蛋白酶活化受體2 、治療誘導衰老
外文關鍵詞： Prevotella intermedia, colorectal cancer, chemoresistance, PAR-2, therapy-induced senescence
相關次數： 點閱：129  下載：0 
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    • 結腸直腸癌是發生率世界排名第三的惡性癌症類型，具有高度的復發和轉移率。近期研究已證實腫瘤微生物是引發化療抗藥性的重要原因之一，進而影響治療效果。中間普雷沃菌（Prevotella intermedia）是一種存在於口腔和腸道的革蘭氏陰性厭氧菌，近年被發現在結腸直腸癌腫瘤中具有較高含量，並與癌症發展有關。然而中間普雷沃菌在結腸直腸癌化療抗藥性中扮演的角色仍未被揭露。本研究中調查了中間普雷沃菌是否促進結腸直腸癌對化療藥5-氟尿嘧啶（5-FU）的抗藥性。中間普雷沃菌ATCC 25611菌株與結腸直腸癌細胞株的共培養，以及其條件培養基（CM）的處理，顯著促進了細胞增殖並降低了對5-氟尿嘧啶的敏感性。CM處理也增強了在化療藥物施用下癌細胞的群落形成能力，顯示出其與化療抗性和復發有很大的潛在相關性。在機制上，中間普雷沃菌分泌的半胱胺酸蛋白酶interpain A能夠活化結腸直腸癌細胞上的蛋白酶活化受體2（PAR-2）。較高interpain A表現水平的中間普雷沃菌臨床分離株的CM具有更強的促增殖和抗藥能力，而蛋白酶抑制劑和PAR-2拮抗劑能顯著抑制這些效應。進一步的細胞傳訊分析顯示，CM介導的效應主要是通過PI3K和AKT傳訊分子驅動的。另外在5-氟尿嘧啶施用下，CM處理會顯著上調藥物外排基因ABCB1的表達，暗示其在外排介導的抗藥性中扮演重要角色。透過SA-β-gal染色的方法進行判斷，CM處理亦增加了治療誘導衰老（TIS）細胞的比例。另外CM處理之細胞上調與衰老相關的細胞因子IL-10與TGF-β的表達量，並可以藉此進一步增強鄰近細胞的旁觀者效應，促進其增殖與抗藥。綜合而言，我們的研究發現揭示了中間普雷沃菌在結腸直腸癌中扮演的新角色，透過PAR-2訊號傳導、ABCB1上調及衰老誘導來促進化療抗藥性，為腫瘤微生物影響結腸直腸癌化療效果提供了新的見解。

    Colorectal cancer (CRC) is the third most common cancer worldwide and is characterized by a high rate of recurrence and metastasis. Recent studies have identified intratumoral microbiota as a critical factor influencing chemotherapy resistance, thereby compromising treatment efficacy. Prevotella intermedia, a Gram-negative anaerobe typically found in the oral cavity and gut, is enriched in CRC tumors and has been associated with advanced disease stages. However, its role in CRC chemoresistance remains largely unexplored. In this study, we investigated whether P. intermedia contributes to CRC resistance to 5-fluorouracil (5-FU). Co-culture of P. intermedia ATCC 25611 with CRC cell lines, as well as treatment with its conditioned medium (CM), significantly promoted cell proliferation and reduced sensitivity to 5-FU. CM treatment also enhances the clonogenicity under drug exposure, indicating potential links to chemoresistance and recurrence. Mechanistically, the cysteine protease interpain A (InpA) secreted by P. intermedia was found to activate protease-activated receptor 2 (PAR-2) on CRC cells. Clinical isolates with higher InpA expression level induced stronger proliferative and chemoresistant responses, while protease inhibitors and PAR-2 antagonists significantly suppressed these effects. Further pathway analysis revealed that CM-mediated effects were primarily driven through PI3K and AKT signaling. Additionally, CM treatment under 5-FU exposure led to upregulation of the drug efflux gene ABCB1, suggesting a role for efflux-mediated drug resistance. CM also increased therapy-induced senescence (TIS), as evidenced by enhanced SA-β-gal staining and elevated expression of the senescence-associated cytokines IL-10 and TGF-β. These changes further enhanced bystander effects, promoting neighboring cell proliferation and resistance. Collectively, our findings reveal a previously unrecognized role of P. intermedia in promoting chemoresistance in CRC via PAR-2 signaling, ABCB1 upregulation, and senescence induction, offering new insights into microbe-driven therapeutic failure in CRC.

    碩士論文合格證明書 1 Abstract 2 中文摘要 4 Acknowledgement 5 Contents 7 Table Contents 12 Figure Contents 13 Chapter 1. Introduction 16 1.1 Colorectal cancer 16 1.2 Intratumoral bacteria 17 1.3 Prevotella intermedia 19 1.3.1 Basic information 19 1.3.2 Secretion systems and proteolytic activity 19 1.3.3 Correlation with cancer 20 1.4 Protease-activated receptors (PARs) 21 1.4.1 Basic information 21 1.4.2 Correlation with cancer 21 1.5 Therapy-induced senescence (TIS) 22 1.6 Specific aim 23 Chapter 2. Materials and Methods 25 2.1 Cell culture 25 2.1.1 Medium preparation 25 2.1.2 Cell line source and cryopreservation 25 2.1.3 Culture conditions 26 2.2 Bacterial strains and culture conditions 26 2.2.1 Medium preparation 26 2.2.2 Bacteria source and cryopreservation 27 2.2.3 Culture Conditions 27 2.2.4 Preparation of P. intermedia conditioned medium (CM) 28 2.3 Chemical reagents 28 2.4 Cell counting and viability assay 29 2.4.1 Cell counting 29 2.4.2 Cell viability assay 30 2.5 Co-culture assay 30 2.6 Colony Formation Assay 30 2.7 IC₅₀ assay 31 2.8 Quantification of cellular mRNA expression 31 2.8.1 Cell sample preparation 31 2.8.2 RNA extraction and cDNA synthesis 31 2.8.3 Reverse transcription quantitative PCR (RT-qPCR) 32 2.9 Detection of senescent cells 33 2.9.1 Cell Sample Preparation 33 2.9.2 Senescence-Associated β-Galactosidase (SA-β-gal) Staining 33 2.10 Microbial Data Acquisition 33 2.11 Statistical Analysis 34 Chapter 3. Results 35 3.1. Prevotella is enriched in colorectal tumors and positively correlates with CRC stage 35 3.2. P. intermedia ATCC 25611 promotes CRC cell proliferation 35 3.3. P. intermedia ATCC 25611 increases the resistance of CRC cells to 5-FU 36 3.4. CM derived from P. intermedia ATCC 25611 promotes CRC cell proliferation and resistance to 5-FU 37 3.5. Prolonged CM treatment further enhances CRC cell proliferation and 5-FU resistance 37 3.6. CM treatment increases the IC₅₀ of CRC cells to 5-FU 38 3.7. CM treatment enhances CRC cell clonogenicity under 5-FU treatment 38 3.8. CM treatment upregulates cyclin D1 and MDR1 mRNA expression under 5-FU treatment 39 3.9. The expression level of InpA and protease activity in P. intermedia CM are positively correlated with CRC cell proliferation and chemoresistance 39 3.10. Cysteine protease is the major effector in P. intermedia ATCC 25611 CM 40 3.11. PAR-2 is an important receptor mediating the effects of P. intermedia ATCC 25611 CM 41 3.12. PI3K is involved in P. intermedia ATCC 25611 CM-induced signaling in cancer cells 41 3.13. AKT is involved in P. intermedia ATCC 25611 CM-induced signaling in cancer cells 42 3.14. P. intermedia ATCC 25611 CM promotes Therapy-induced senescence (TIS) cell formation and upregulates SASP expression 43 3.15. P. intermedia ATCC 25611 CM enhances the TIS-associated bystander effect, promoting nearby cell survival and resistance 44 Chapter 4. Discussion 45 4.1 Differences between cell lines 45 4.2 Alternative mechanisms of P. intermedia action 47 4.3 A novel interaction of intratumoral bacteria 50 4.4 Optimization of experimental methods 51 4.4.1 CM Preparation 51 4.4.2 Observation of Therapy-induced senescence Cells 52 4.5 Future Perspectives 53 Chapter 5. Reference 54 Chapter 6. Figures and Tables 62 Chapter 7. Supplementary material and methods 88 7.1 Phosphate-buffered saline (PBS) preparation 88 7.2 P. intermedia ATCC 25611 growth curves 88 7.3 P. intermedia OD value and CFU number curve 88 7.4 Effects of 5-FU on P. intermedia ATCC 25611 growth 89 Chapter 8. Supplementary figures 90

    1. Bray, F., et al., Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians, 2024. 74(3): p. 229-263.
    2. Hossain, M.S., et al., Colorectal cancer: a review of carcinogenesis, global epidemiology, current challenges, risk factors, preventive and treatment strategies. Cancers, 2022. 14(7): p. 1732.
    3. Longley, D.B., D.P. Harkin, and P.G. Johnston, 5-fluorouracil: mechanisms of action and clinical strategies. Nature reviews cancer, 2003. 3(5): p. 330-338.
    4. Gottesman, M.M., T. Fojo, and S.E. Bates, Multidrug resistance in cancer: role of ATP–dependent transporters. Nature reviews cancer, 2002. 2(1): p. 48-58.
    5. Gustavsson, B., et al., A review of the evolution of systemic chemotherapy in the management of colorectal cancer. Clinical colorectal cancer, 2015. 14(1): p. 1-10.
    6. Hammond, W.A., A. Swaika, and K. Mody, Pharmacologic resistance in colorectal cancer: a review. Therapeutic advances in medical oncology, 2016. 8(1): p. 57-84.
    7. Giraldo, N.A., et al., The clinical role of the TME in solid cancer. British journal of cancer, 2019. 120(1): p. 45-53.
    8. LaCourse, K.D., C.D. Johnston, and S. Bullman, The relationship between gastrointestinal cancers and the microbiota. The Lancet Gastroenterology & Hepatology, 2021. 6(6): p. 498-509.
    9. Yang, L., et al., Intratumoral microbiota: roles in cancer initiation, development and therapeutic efficacy. Signal Transduction and Targeted Therapy, 2023. 8(1): p. 35.
    10. Yu, T., et al., Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. Cell, 2017. 170(3): p. 548-563. e16.
    11. Lo, C.-H., et al., Enrichment of Prevotella intermedia in human colorectal cancer and its additive effects with Fusobacterium nucleatum on the malignant transformation of colorectal adenomas. Journal of Biomedical Science, 2022. 29(1): p. 88.
    12. Schorr, L., et al., Intracellular bacteria in cancer—prospects and debates. npj Biofilms and Microbiomes, 2023. 9(1): p. 76.
    13. Galeano Niño, J.L., et al., Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer. Nature, 2022. 611(7937): p. 810-817.
    14. Wang, G., X. He, and Q. Wang, Intratumoral bacteria are an important “accomplice” in tumor development and metastasis. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 2023. 1878(1): p. 188846.
    15. Bullman, S., et al., Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science, 2017. 358(6369): p. 1443-1448.
    16. He, Z., et al., Campylobacter jejuni promotes colorectal tumorigenesis through the action of cytolethal distending toxin. Gut, 2019. 68(2): p. 289-300.
    17. Frankel, T.L. and M.P. di Magliano, Immune sensing of microbial metabolites: Action at the tumor. Immunity, 2022. 55(2): p. 192-194.
    18. Ternes, D., et al., Microbiome in colorectal cancer: how to get from meta-omics to mechanism? Trends in microbiology, 2020. 28(5): p. 401-423.
    19. Lehouritis, P., et al., Local bacteria affect the efficacy of chemotherapeutic drugs. Scientific reports, 2015. 5(1): p. 14554.
    20. Zhang, S., et al., Fusobacterium nucleatum promotes chemoresistance to 5-fluorouracil by upregulation of BIRC3 expression in colorectal cancer. Journal of Experimental & Clinical Cancer Research, 2019. 38: p. 1-13.
    21. LaCourse, K.D., et al., The cancer chemotherapeutic 5-fluorouracil is a potent Fusobacterium nucleatum inhibitor and its activity is modified by intratumoral microbiota. Cell Reports, 2022. 41(7).
    22. Geller, L.T., et al., Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science, 2017. 357(6356): p. 1156-1160.
    23. SHAH, H.N. and D.M. COLLINS, Prevotella, a new genus to include Bacteroides melaninogenicus and related species formerly classified in the genus Bacteroides. International journal of systematic and evolutionary microbiology, 1990. 40(2): p. 205-208.
    24. Vieira, R.W., Cardiovascular and periodontal diseases. 2014, SciELO Brasil. p. VII-IX.
    25. Zhang, S., et al., Current research progress on Prevotella intermedia and associated diseases. Critical Reviews in Microbiology, 2024: p. 1-18.
    26. Dorn, B.R., K.-P. Leung, and A. Progulske-Fox, Invasion of human oral epithelial cells by Prevotella intermedia. Infection and immunity, 1998. 66(12): p. 6054-6057.
    27. Yamanaka, T., et al., Gene expression profile and pathogenicity of biofilm-forming Prevotella intermedia strain 17. BMC microbiology, 2009. 9: p. 1-15.
    28. Gursoy, U., E. Könönen, and V.J. Uitto, Prevotella intermedia ATCC 25611 targets host cell lamellipodia in epithelial cell adhesion and invasion. Oral microbiology and immunology, 2009. 24(4): p. 304-309.
    29. Sengupta, D., et al., Interaction of Prevotella intermedia strain 17 leucine-rich repeat domain protein AdpF with eukaryotic cells promotes bacterial internalization. Infection and Immunity, 2014. 82(6): p. 2637-2648.
    30. Yu, F., et al., Identification and characterization of a cell surface protein of Prevotella intermedia 17 with broad‐spectrum binding activity for extracellular matrix proteins. Proteomics, 2006. 6(22): p. 6023-6032.
    31. Naito, M., et al., Insertional inactivation and gene complementation of Prevotella intermedia type IX secretion system reveals its indispensable roles in black pigmentation, hemagglutination, protease activity of interpain A, and biofilm formation. Journal of Bacteriology, 2022. 204(8): p. e00203-22.
    32. Karched, M., et al., Proteomic analysis of the periodontal pathogen Prevotella intermedia secretomes in biofilm and planktonic lifestyles. Scientific Reports, 2022. 12(1): p. 5636.
    33. Eley, B.M. and S.W. Cox, Proteolytic and hydrolytic enzymes from putative periodontal pathogens: characterization, molecular genetics, effects on host defenses and tisues and detection in gingival crevice fluid. Periodontology 2000, 2003. 31(1).
    34. Sharma, G., et al., Prevotella: An insight into its characteristics and associated virulence factors. Microbial Pathogenesis, 2022. 169: p. 105673.
    35. Mallorquí-Fernández, N., et al., A new autocatalytic activation mechanism for cysteine proteases revealed by Prevotella intermedia interpain A. Journal of Biological Chemistry, 2008. 283(5): p. 2871-2882.
    36. Potempa, M., et al., Interpain A, a cysteine proteinase from Prevotella intermedia, inhibits complement by degrading complement factor C3. PLoS pathogens, 2009. 5(2): p. e1000316.
    37. Chang, S.-M., et al., The protease interpain A of Prevotella intermedia promotes human OSCC cells proliferation and migration. bioRxiv, 2024: p. 2024.10. 20.619282.
    38. Senthakumaran, T., et al., Microbial dynamics with CRC progression: a study of the mucosal microbiota at multiple sites in cancers, adenomatous polyps, and healthy controls. European Journal of Clinical Microbiology & Infectious Diseases, 2023. 42(3): p. 305-322.
    39. Dai, Z., et al., Multi-cohort analysis of colorectal cancer metagenome identified altered bacteria across populations and universal bacterial markers. Microbiome, 2018. 6: p. 1-12.
    40. Wong, S.H. and J. Yu, Gut microbiota in colorectal cancer: mechanisms of action and clinical applications. Nature reviews Gastroenterology & hepatology, 2019. 16(11): p. 690-704.
    41. Hou, X.Y., et al., Prevotella contributes to individual response of FOLFOX in colon cancer. Clinical and Translational Medicine, 2021. 11(9): p. e512.
    42. Peach, C.J., et al., Protease-activated receptors in health and disease. Physiological Reviews, 2023. 103(1): p. 717-785.
    43. Morris, D.R., et al., Protease-activated receptor-2 is essential for factor viia and xa–induced signaling, migration, and invasion of breast cancer cells. Cancer research, 2006. 66(1): p. 307-314.
    44. Böhm, S.K., et al., Molecular cloning, expression and potential functions of the human proteinase-activated receptor-2. Biochemical Journal, 1996. 314(3): p. 1009-1016.
    45. Ma, Y., et al., MicroRNA-34a mediates the autocrine signaling of PAR2-activating proteinase and its role in colonic cancer cell proliferation. PloS one, 2013. 8(8): p. e72383.
    46. Patnaik, R., et al., Targeting PAR-2-driven inflammatory pathways in colorectal cancer: mechanistic insights from atorvastatin and rosuvastatin treatment in cell line models. Translational Cancer Research, 2025. 14(3): p. 1531.
    47. Darmoul, D., et al., Protease-activated receptor 2 in colon cancer: trypsin-induced MAPK phosphorylation and cell proliferation are mediated by epidermal growth factor receptor transactivation. Journal of Biological Chemistry, 2004. 279(20): p. 20927-20934.
    48. Iablokov, V., et al., Proteinase-activated receptor 2 (PAR2) decreases apoptosis in colonic epithelial cells. Journal of Biological Chemistry, 2014. 289(49): p. 34366-34377.
    49. Quan, Q., et al., PAR2 inhibition enhanced the sensitivity of colorectal cancer cells to 5-FU and reduced EMT signaling. Oncology Research, 2019. 27(7): p. 779.
    50. Jochems, F., et al., The Cancer SENESCopedia: A delineation of cancer cell senescence. Cell reports, 2021. 36(4).
    51. Cuollo, L., et al., The senescence-associated secretory phenotype (SASP) in the challenging future of cancer therapy and age-related diseases. Biology, 2020. 9(12): p. 485.
    52. Muñoz-Espín, D. and M. Serrano, Cellular senescence: from physiology to pathology. Nature reviews Molecular cell biology, 2014. 15(7): p. 482-496.
    53. Lee, B.Y., et al., Senescence‐associated β‐galactosidase is lysosomal β‐galactosidase. Aging cell, 2006. 5(2): p. 187-195.
    54. Reimann, M., S. Lee, and C.A. Schmitt, Cellular senescence: Neither irreversible nor reversible. Journal of Experimental Medicine, 2024. 221(4): p. e20232136.
    55. Ewald, J.A., et al., Therapy-induced senescence in cancer. JNCI: Journal of the National Cancer Institute, 2010. 102(20): p. 1536-1546.
    56. Chambers, C.R., et al., Overcoming the senescence‐associated secretory phenotype (SASP): a complex mechanism of resistance in the treatment of cancer. Molecular oncology, 2021. 15(12): p. 3242-3255.
    57. Tato-Costa, J., et al., Therapy-induced cellular senescence induces epithelial-to-mesenchymal transition and increases invasiveness in rectal cancer. Clinical colorectal cancer, 2016. 15(2): p. 170-178. e3.
    58. Kehagias, P., et al., Regorafenib induces senescence and epithelial-mesenchymal transition in colorectal cancer to promote drug resistance. Cells, 2022. 11(22): p. 3663.
    59. Chen, K.-P., et al., BIC: a database for the transcriptional landscape of bacteria in cancer. Nucleic acids research, 2023. 51(D1): p. D1205-D1211.
    60. Dohlman, A.B., et al., The cancer microbiome atlas: a pan-cancer comparative analysis to distinguish tissue-resident microbiota from contaminants. Cell host & microbe, 2021. 29(2): p. 281-298. e5.
    61. Nejman, D., et al., The human tumor microbiome is composed of tumor type–specific intracellular bacteria. Science, 2020. 368(6494): p. 973-980.
    62. Palmieri, V., et al., Mechanical and structural comparison between primary tumor and lymph node metastasis cells in colorectal cancer. Soft matter, 2015. 11(28): p. 5719-5726.
    63. Liefers, G.-J., et al., Micrometastases and survival in stage II colorectal cancer. New England Journal of Medicine, 1998. 339(4): p. 223-228.
    64. Yoon, W.-H., et al., The tumorigenic, invasive and metastatic potential of epithelial and round subpopulations of the SW480 human colon cancer cell line. Molecular Medicine Reports, 2008. 1(5): p. 763-768.
    65. Fleming-de-Moraes, C.D., et al., Crosstalk between PI3K/Akt and Wnt/β-catenin pathways promote colorectal cancer progression regardless of mutational status. Cancer biology & therapy, 2022. 23(1): p. 1-13.
    66. Huang, Y.-L., et al., Isoliquiritigenin inhibits colorectal cancer cells HCT-116 growth by suppressing the PI3K/AKT pathway. Open Life Sciences, 2017. 12(1): p. 300-307.
    67. Ahmed, D., et al., Epigenetic and genetic features of 24 colon cancer cell lines. Oncogenesis, 2013. 2(9): p. e71-e71.
    68. Lee, J.A., et al., Differential immune microenvironmental features of microsatellite-unstable colorectal cancers according to Fusobacterium nucleatum status. Cancer Immunology, Immunotherapy, 2021. 70: p. 47-59.
    69. Doke, M., et al., Nucleases from Prevotella intermedia can degrade neutrophil extracellular traps. Molecular oral microbiology, 2017. 32(4): p. 288-300.
    70. Liu, J., P. Charles Lin, and B. P Zhou, Inflammation fuels tumor progress and metastasis. Current pharmaceutical design, 2015. 21(21): p. 3032-3040.
    71. Ye, X., et al., Ultrastructural and glycoproteomic characterization of Prevotella intermedia: Insights into O‐glycosylation and outer membrane vesicles. MicrobiologyOpen, 2024. 13(2): p. e1401.
    72. Zhou, B., et al., Activation of PAR2 or/and TLR4 promotes SW620 cell proliferation and migration via phosphorylation of ERK1/2. Oncology reports, 2011. 25(2): p. 503-511.
    73. Woo, B.H., et al., Oral cancer cells sustainedly infected with Porphyromonas gingivalis exhibit resistance to Taxol and have higher metastatic potential. Oncotarget, 2017. 8(29): p. 46981.
    74. Milanovic, M., et al., Senescence-associated reprogramming promotes cancer stemness. Nature, 2018. 553(7686): p. 96-100.
    75. Davis Jr, J.E., et al., Tumor dormancy and slow-cycling cancer cells. Human cell transformation: advances in cell models for the study of cancer and aging, 2019: p. 199-206.
    76. Wang, Q., et al., Fusobacterium nucleatum promotes colorectal cancer through neogenesis of tumor stem cells. The Journal of Clinical Investigation, 2025. 135(3).
    77. Liu, H., et al., Fusobacterium nucleatum promotes colorectal cancer cell to acquire stem cell‐like features by manipulating lipid droplet‐mediated numb degradation. Advanced Science, 2022. 9(12): p. 2105222.
    78. Wang, Q., et al., Fusobacterium nucleatum produces cancer stem cell characteristics via EMT-resembling variations. International Journal of Clinical and Experimental Pathology, 2020. 13(7): p. 1819.
    79. Yu, M.R., H.J. Kim, and H.R. Park, Fusobacterium nucleatum accelerates the progression of colitis-associated colorectal cancer by promoting EMT. Cancers, 2020. 12(10): p. 2728.
    80. Ha, S., et al., PAR2‐mediated cellular senescence promotes inflammation and fibrosis in aging and chronic kidney disease. Aging Cell, 2024. 23(8): p. e14184.
    81. De Dosso, S., et al., Preoperative metronidazole treatment to evaluate its efficacy in reducing Fusobacterium nucleatum colonisation in colorectal cancer patients: a proof-of-concept trial. ESMO Gastrointestinal Oncology, 2025. 8: p. 100169.
    82. Gao, R.Q., et al., A prospective, single-centre, randomized, double-blind controlled study protocol to study whether long-term oral metronidazole can effectively reduce the incidence of postoperative liver metastasis in patients with colorectal cancer. Trials, 2023. 24(1): p. 786.

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