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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 沈湯龍 | zh_TW |
| dc.contributor.advisor | Tang-Long Shen | en |
| dc.contributor.author | 黃品皓 | zh_TW |
| dc.contributor.author | Pin-Hao Huang | en |
| dc.date.accessioned | 2025-08-19T16:15:26Z | - |
| dc.date.available | 2025-09-17 | - |
| dc.date.copyright | 2025-08-19 | - |
| dc.date.issued | 2025 | - |
| dc.date.submitted | 2025-08-08 | - |
| dc.identifier.citation | Becker, W. R., Nevins, S. A., Chen, D. C., Chiu, R., Horning, A. M., Guha, T. K., Laquindanum, R., Mills, M., Chaib, H., & Ladabaum, U. (2022). Single-cell analyses define a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer. Nature genetics, 54(7), 985–995.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/98801 | - |
| dc.description.abstract | 結直腸息肉是結直腸癌（CRC）的前驅病變，了解其分子異質性有助於揭示結直腸癌早期惡性轉化的機制。本研究收集18例結直腸息肉及5例正常黏膜樣本，進行轉錄體分析。結果顯示，息肉在基因表現、路徑活化與腫瘤微環境（TME）組成上呈現出與CMS2型與CMS4型結直腸癌相似的二元分化特徵。其中，我們發現THBS2為驅動上皮–間質轉化（EMT）的關鍵因子，其透過 integrin αVβ3–FAK訊號通路發揮作用，且其表現量與息肉癌症率呈正相關 (R2 = 0.84，P = 0.03)。泛癌分析支持 THBS2 為結直腸息肉與癌症的預後標誌。單細胞轉錄體分析進一步揭示出一群具特徵性的 THBS2⁺ 癌相關纖維母細胞（CAF），參與腫瘤微環境中早期的細胞外基質（ECM）重塑。體外實驗證實，rhTHBS2及Thbs2過表達之條件培養基（CM）促進CMS4大腸癌細胞Caco-2及HCT116的腫瘤形成、跨膜遷移及侵襲能力。值得注意的是，藉由藥物重定位所辨識出的 GW0742 能抑制rhTHBS2造成的細胞遷移。整合mRNA、lncRNA、miRNA、circRNA的WGCNA分析指出，ncRNA參與THBS2調控的惡性轉型。綜上所述，CRC 的預後可能在癌症發生前即已被THBS2⁺ CAF 所主導的腫瘤微環境塑形，並指出THBS2及其調控網路為早期干預與預後評估的潛在標誌物。 | zh_TW |
| dc.description.abstract | Colorectal polyps are precancerous lesions of CRC, yet their molecular heterogeneity and links to CRC subtypes remain unclear. We analyzed bulk transcriptomes of 18 colorectal polyps and 5 normal controls, revealing a dichotomous pattern in gene expression, pathway activation, and TME composition resembling CMS2 and CMS4 CRC. THBS2 drives EMT via integrin αVβ3–FAK and correlates with polyp cancer rates (R² = 0.84, P = 0.03). Pan-cancer analyses supported THBS2 as a prognostic marker for both polyps and CRC. Single-cell transcriptomics further revealed a distinct THBS2⁺ cancer-associated fibroblast (CAF) population implicated in early extracellular matrix (ECM) remodeling within the TME. In vitro, rhTHBS2/Thbs2 OE fibroblast CM promotes tumorigenesis, migration and invasion in CMS4 CRC cells; while GW0742, a drug identified through repurposing, reverses these effects. Integrative WGCNA of multi-RNA reveals ncRNA networks underpinning THBS2-driven transformation. These findings suggest that CRC prognostic fate may be preconfigured by THBS2⁺ CAFs before cancer onset and nominate THBS2 and its regulatory circuit as early biomarkers and therapeutic targets. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2025-08-19T16:15:26Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2025-08-19T16:15:26Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 口試委員審定書 II
致謝 III 摘要 IV Abstract V Contents VI The list of figures IX The list of tables XI Introduction 1 1.1 Colorectal cancer and concensus molecular subtypes 1 1.2 Classification, prognosis and molecular features of colorectal polyps 2 1.3 Malignant transformation mechanisms 3 1.4 Research aims 4 Materials and methods 6 2.1 Clinical samples 6 2.2 Library preparation and next generation sequencing 7 2.2.1 Messenger RNA (mRNA) and long non-coding RNA (lncRNA) 7 2.2.3 MicroRNA (miRNA) 8 2.2.3 Circular RNA (circRNA) 8 2.3 RNA-seq variant calling 9 2.4 Transcriptomic analysis 10 2.5 Pan-cancer analysis 11 2.6 Single cell transcriptomic analysis 11 2.7 Immunohistochemistry (IHC) staining 12 2.8 Cell culture 13 2.9 Conditioned Medium Collection and Protein Fractionation 13 2.10 Plasmids and transfection 14 2.11 RNA extraction and quantitative real-time polymerase chain reaction (qPCR) 15 2.12 Western blot 15 2.13 Functional assays 16 2.14 Drug repurposing 17 2.15 Molecular docking 17 2.16 Weighted gene co-expression network analysis (WGCNA) 18 Results 20 3.1 Clinicopathological characteristics of colorectal polyp subtypes 20 3.2 A dichotomous transcriptomic programs in colorectal polyp subtypes 21 3.3 Shared and distinct pathway activation patterns link polyp subtypes to consensus molecular subtypes (CMS) of CRC 22 3.4 Tumor-microenvironment analysis corroborates CMS4-like stromal activation in LST-NG and DN polyps 23 3.5 THBS2 emerged as a potential driver of EMT and is positively correlated with colorectal polyp cancer rates 24 3.6 Pan-cancer analysis reveals prognostic value of THBS2 in colorectal polyps and CRC 26 3.7 Single-cell transcriptomic analysis identifies THBS2⁺ matrix CAFs as the primary source of THBS2 in colorectal cancer 27 3.8 THBS2 promotes colonogenesis and migration of CMS4 CRC in vitro 29 3.9 Structure-guided repurposing identified the PPAR-δ agonist GW0742 as a nanomolar THBS2 binder and concentration-dependent modulator of THBS2-driven motility 30 3.10 WGCNA reveals a key ncRNA co-expression module associated with polyp malignancy and THBS2 32 Discussion 33 4.1 Implications of the dichotomous molecular and stromal patterns in colorectal polyps 33 4.2 Role of THBS2 in malignant transformation of colorectal polyps 34 4.3 Mechanistic complexity of THBS2-mediated pro-tumor signaling 36 4.4 Translational potential of THBS2 as a biomarker and therapeutic target 37 4.5 Clinical relevance of THBS2⁺ mCAFs in residual disease and PCCRC 38 4.6 Repurposing GW0742 as a THBS2 antagonist in CMS4 CRC 38 Conclusion 40 References 41 Tables 48 Figures 49 Appendix 66 | - |
| dc.language.iso | en | - |
| dc.subject | 結直腸癌 | zh_TW |
| dc.subject | 結直腸息肉 | zh_TW |
| dc.subject | THBS2 | zh_TW |
| dc.subject | integrin αVβ3 | zh_TW |
| dc.subject | cancer associated fibroblast | zh_TW |
| dc.subject | GW0742 | zh_TW |
| dc.subject | THBS2 | en |
| dc.subject | colorectal cancer | en |
| dc.subject | GW0742 | en |
| dc.subject | cancer associated fibroblast | en |
| dc.subject | integrin αVβ3 | en |
| dc.subject | colorectal polyps | en |
| dc.title | Thrombospondin 2（THBS2）表現之癌症相關成纖維細胞驅動結直腸息肉的惡性轉化 | zh_TW |
| dc.title | Thrombospondin 2 (THBS2)–positive cancer-associated fibroblasts drive the malignant transformation of colorectal polyps | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 113-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 陳倩瑜;邱瀚模 | zh_TW |
| dc.contributor.oralexamcommittee | Chien-Yu Chen;Han-Mo Chiu | en |
| dc.subject.keyword | 結直腸癌,結直腸息肉,THBS2,integrin αVβ3,cancer associated fibroblast,GW0742, | zh_TW |
| dc.subject.keyword | colorectal cancer,colorectal polyps,THBS2,integrin αVβ3,cancer associated fibroblast,GW0742, | en |
| dc.relation.page | 86 | - |
| dc.identifier.doi | 10.6342/NTU202503687 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2025-08-12 | - |
| dc.contributor.author-college | 生物資源暨農學院 | - |
| dc.contributor.author-dept | 植物病理與微生物學系 | - |
| dc.date.embargo-lift | N/A | - |
| 顯示於系所單位： | 植物病理與微生物學系 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-113-2.pdf 未授權公開取用 | 40.47 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。