본문 바로가기
KERD
논문KCI 등재

Increased Expression of Thymosin β4 Is Independently Correlated with Hypoxia Inducible Factor-1α (HIF-1α) and Worse Clinical Outcome in Human Colorectal Cancer

1

조회

0

다운로드

0

인용

0

참고문헌

키워드

주제분류병리학

초록

Background: Thymosin β4 is a multi-functional hormone-like polypeptide, being involved in cell migration, angiogenesis, and tumor metastasis. This study was undertaken to clarify the clinicopathologic implications of thymosin β4 expression in human colorectal cancers (CRCs). Methods: We investigated tissue sections from 143 patients with CRC by immunohistochemistry. In addition, we evaluated the expression patterns and the clinico-pathological significance of thymosin β4 expression in association with hypoxia inducible factor-1α (HIF-1α) expression in the CRC series. Results: High expression of thymosin β4 was significantly correlated with lymphovascular invasion, invasion depth, regional lymph node metastasis, distant metastasis, and TNM stage. Patients with high expression of thymosin β4 showed poor recurrence-free survival (p = .001) and poor overall survival (p = .005) on multivariate analysis. We also found that thymosin β4 and HIF-1α were overexpressed and that thymosin β4 expression increased in parallel with HIF-1α expression in CRC. Conclusions: A high expression level of thymosin β4 indicates poor clinical outcomes and may be a useful prognostic factor in CRC. Thymosin β4 is functionally related with HIF-1α and may be a potentially valuable biomarker and possible therapeutic target for CRC.

Abstract

Background: Thymosin β4 is a multi-functional hormone-like polypeptide, being involved in cell migration, angiogenesis, and tumor metastasis. This study was undertaken to clarify the clinicopathologic implications of thymosin β4 expression in human colorectal cancers (CRCs). Methods: We investigated tissue sections from 143 patients with CRC by immunohistochemistry. In addition, we evaluated the expression patterns and the clinico-pathological significance of thymosin β4 expression in association with hypoxia inducible factor-1α (HIF-1α) expression in the CRC series. Results: High expression of thymosin β4 was significantly correlated with lymphovascular invasion, invasion depth, regional lymph node metastasis, distant metastasis, and TNM stage. Patients with high expression of thymosin β4 showed poor recurrence-free survival (p = .001) and poor overall survival (p = .005) on multivariate analysis. We also found that thymosin β4 and HIF-1α were overexpressed and that thymosin β4 expression increased in parallel with HIF-1α expression in CRC. Conclusions: A high expression level of thymosin β4 indicates poor clinical outcomes and may be a useful prognostic factor in CRC. Thymosin β4 is functionally related with HIF-1α and may be a potentially valuable biomarker and possible therapeutic target for CRC.

참고문헌 (42)

  1. Cannito S, "Redox mechanisms switch on hypoxia-dependent epithelial-mesenchymal transition in cancer cells", Carcinogenesis, 29, pp.2267~2278 (2008)
  2. Lluis JM, "Dual role of mitochondrial reactive oxygen species in hypoxia signaling: activation of nuclear factor-κB via c-SRC and oxidant-dependent cell death", Cancer Res, 67, pp.7368~7377 (2007)
  3. Sansone P, "Cyclooxygenase-2", carbonic anhydrase-IX up-regulation promotes invasive potential and hypoxia survival in colorectal cancer cells, 2009, pp.13, 3876~3887
  4. To KK, "Genetic instability: the dark side of the hypoxic response", Cell Cycle, 4, pp.881~882 (2005)
  5. Huang LE, "Hypoxia-induced genetic instability: a calculated mechanism underlying tumor progression", J Mol Med (Berl), 85, pp.139~148 (2007)
  6. Bristow RG, "Hypoxia and metabolism: hypoxia, DNA repair and genetic instability", Nat Rev Cancer, 8, pp.180~192 (2008)
  7. Oh JM, "Hypoxia-inducible transcription factor (HIF)-1 alpha stabilization by actin-sequestering protein, thymosin beta-4 (TB4) in Hela cervical tumor cells", Cancer Lett, 264, pp.29~35 (2008)
  8. Koukourakis MI, "Lactate dehydrogenase 5 (LDH5) relates to up-regulated hypoxia inducible factor pathway and metastasis in colorectal cancer", Clin Exp Metastasis, 22, pp.25~30 (2005)
  9. Sivridis E, "Proliferating fibroblasts at the invading tumour edge of colorectal adenocarcinomas are associated with endogenous markers of hypoxia, acidity, and oxidative stress", J Clin Pathol, 58, pp.1033~1038 (2005)
  10. Giles RH, "Interplay between VHL", HIF1alpha and Wnt, Oncogene, pp.2006, 25[DOI]
  11. Koukourakis MI, "Endogenous markers of hypoxia", anaerobic metabolism and anemia in primary colorectal cancer, 2006, pp.97, 582~588
  12. Huff T, "Beta-thymosins, small acidic peptides with multiple functions", Int J Biochem Cell Biol, 33, pp.205~220 (2001)
  13. Kobayashi T, "Thymosin-beta4 regulates motility and metastasis of malignant mouse fibrosarcoma cells", Am J Pathol, 160, pp.869~882 (2002)
  14. Clark EA, "Genomic analysis of metastasis reveals an essential role for RhoC", Nature, 406, pp.532~535 (2000)
  15. Xie D, "Discovery of over-expressed genes and genetic alterations in breast cancer cells using a combination of suppression subtractive hybridization, multiplex FISH and comparative genomic hybridization", Int J Oncol, 21, pp.499~507 (2002)
  16. 김루시아, "위샘암 환자의 예후 인자로서 Thymosin-β4의 용성", Journal of Pathology and Translational Medicine, 41(3), pp.176~182 (2007), 대한병리학회
  17. Hsiao HL, "Overexpression of thymosin beta-4 renders SW480 colon carcinoma cells more resistant to apoptosis triggered by FasL and two topoisomerase II inhibitors via downregulating Fas and upregulating Survivin expression, respectively", Carcinogenesis, 27, pp.936~944 (2006)
  18. Huang HC, "Thymosin beta4 triggers an epithelial-mesenchymal transition in colorectal carcinoma by upregulating integrin-linked kinase", Oncogene, 26, pp.2781~2790 (2007)
  19. Wang WS, "Overexpression of the thymosin beta-4 gene is associated with malignant progression of SW480 colon cancer cells", Oncogene, 22, pp.3297~3306 (2003)
  20. Wang WS, "Overexpression of the thymosin beta-4 gene is associated with increased invasion of SW480 colon carcinoma cells and the distant metastasis of human colorectal carcinoma", Oncogene, 23, pp.6666~6671 (2004)
  21. Wang WS, "Colorectal carcinoma: from tumorigenesis to treatment", Cell Mol Life Sci, 63, pp.663~671 (2006)
  22. Piao Z, "Thymosin beta4 induces invasion and migration of human colorectal cancer cells through the ILK", AKT, Biochem Biophys Res Commun, pp.2014, 452[DOI]
  23. Kang YJ, "Thymosin beta4 was upregulated in recurred colorectal cancers", J Clin Pathol, 67, pp.188~190 (2014)
  24. Yoon SY, "Thymosin beta4 expression correlates with lymph node metastasis through hypoxia inducible factor-alpha induction in breast cancer", Oncol Rep, 25, pp.23~31 (2011)
  25. Washington MK, "Protocol for the examination of specimens from patients with primary carcinoma of the colon and rectum", Arch Pathol Lab Med, 133, pp.1539~1551 (2009)
  26. Prall F, "Tumour budding in colorectal carcinoma", Histopathology, 50, pp.151~162 (2007)
  27. Wang LM, "Tumor budding is a strong and reproducible prognostic marker in T3N0 colorectal cancer", Am J Surg Pathol, 33, pp.134~141 (2009)
  28. Puppa G, "TNM staging system of colorectal carcinoma: surgical pathology of the seventh edition", Diagn Histopathol, 17, pp.243~262 (2011)
  29. Höckel M, "Biological consequences of tumor hypoxia", Semin Oncol, 28(2 Suppl 8), pp.36~41 (2001)
  30. Foo SS, "Functional imaging of intratumoral hypoxia", Mol Imaging Biol, 6, pp.291~305 (2004)
  31. Mabjeesh NJ, "Hypoxia-inducible factor (HIF) in human tumorigenesis", Histol Histopathol, 22, pp.559~572 (2007)
  32. Lee JW, "Hypoxia", reoxygenation-experienced cancer cell migration and metastasis are regulated by Rap1- and Rac1-GTPase activation via the expression of thymosin beta-4, 2015, pp.6, 9820~9833
  33. Tang MC, "Thymosin beta 4 induces colon cancer cell migration and clinical metastasis via enhancing ILK", IQGAP1, Cancer Lett, pp.2011, 308[DOI]
  34. Nemolato S, "Thymosin beta 4 in colorectal cancer is localized predominantly at the invasion front in tumor cells undergoing epithelial mesenchymal transition", Cancer Biol Ther, 13, pp.191~197 (2012)
  35. Jo JO, "Thymosin beta4 induces the expression of vascular endothelial growth factor (VEGF) in a hypoxia-inducible factor (HIF)-1alpha-dependent manner", Biochim Biophys Acta, 1803, pp.1244~1251 (2010)
  36. Brahimi-Horn MC, "HIF at a glance", J Cell Sci, 122(Pt 8), pp.1055~1057 (2009)
  37. Ryan HE, "Hypoxia-inducible factor1alpha is a positive factor in solid tumor growth", Cancer Res, 60, pp.4010~4015 (2000)
  38. Swami M, "Hypoxia: the HIF2alpha puzzle", Nat Rev Cancer, 10, pp.603~ (2010)
  39. Gu YZ, "Molecular characterization and chromosomal localization of a third alpha-class hypoxia inducible factor subunit, HIF3alpha", Gene Expr, 7, pp.205~213 (1998)
  40. Kietzmann T, "Perivenous expression of the mRNA of the three hypoxia-inducible factor alpha-subunits, HIF1alpha, HIF2alpha and HIF3alpha, in rat liver", Biochem J, 354(Pt 3), pp.531~537 (2001)
  41. Clottes E, "Hypoxia-inducible factor 1: regulation, involvement in carcinogenesis and target for anticancer therapy", Bull Cancer, 92, pp.119~127 (2005)
  42. Zhong H, "Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases", Cancer Res, 59, pp.5830~5835 (1999)

관련 논문AI추천

The Clinicopathological Significance of Tissue Levels of Hypoxia-Inducible Factor-1α and Vascular Endothelial Growth Factor in Gastric CancerJoo Ho Lee, Ki-Nam Shim, Kwon Yoo, Seong-Eun Kim, Sung-Ae Jung거트앤리버 소화기연관학회협의회 · Gut and Liver2009 · 제3권 제2호상피성 난소암에서 혈관신생인자로서 Thymosin B4의발현에 관한 연구김아리, 김종일, 문혜성, 전선희, 정혜원대한산부인과학회 · Obstetrics & Gynecology Science2008 · 제51권 제5호Expression of Cortactin and Focal Adhesion Kinase in Colorectal Adenocarcinoma: Correlation with Clinicopathologic Parameters and Their Prognostic Implication강명재, 김요나, 문우성, 박호성, 배준상, 이동근, 장규윤, 정명자, 최지은대한병리학회 · Journal of Pathology and Translational Medicine2012 · 제46권 제5호Clinical and Prognostic Value of TIMP1 in Colorectal Cancer문혁준, 이재호, 이준채, 차유준대한체질인류학회 · 해부·생물인류학2025 · 제38권 제4호Expression of Cyclooxygenase-2 and Tumor Microvessel Density in Colorectal Cancer손진희, 이봉화, 채승완, Eo Jin Kim, Eun Yoon Cho대한암학회 · Cancer Research and Treatment2003 · 제35권 제5호Relationship between the Endogenous Hypoxic Markers Hypoxia Inducible Factor-1α, Carbonic Anhydrase IX, and Epithelial Mesenchymal Transition Regulator TWIST Expression in Non-small Cell Lung Cancer김영대, 박원영, 신동훈, 이민기, 이정희, 이창훈, 정성묵대한병리학회 · Journal of Pathology and Translational Medicine2010 · 제44권 제5호

이 간행물의 다른 논문 (14건)