探討第一型血基質氧化酶對前列腺癌與肺部上皮細胞癌轉移的影響

Up-regulation of heme oxygenase-1 induces migration and invasion in PC-3 and A549 tumor cells

陳文樑(Wen-Lian Chen)

指導教授 ： 符文美

國立臺灣大學/醫學院/藥理學研究所/碩士(2007年)

https://doi.org/10.6342/NTU.2007.01197

摘要

血基質氧化酶 (Heme oxygenase)是把體內的原血紅素 (heme)代謝成biliverdin、一氧化碳 (CO)、及鐵離子 (Fe2+)的速率決定步驟。之後biliverdin會被biliverdin reductase還原成具有抗氧化作用的膽色素 (bilirubin)。最近已有許多研究顯示，Heme oxygenase-1 (HO-1)在細胞保護以及許多正常生理功能中扮演著重要的角色，然而HO-1與癌細胞轉移的關係尚未被清楚地研究。在本篇論文中，我們利用hemin增加PC-3與A549這兩株癌細胞的HO-1表現量來探討HO-1在癌細胞轉移所扮演的角色。實驗結果顯示，藉由hemin增加HO-1可以使PC-3和A549的細胞移行以及入侵能力增加。另一方面，hemin也可以增加其IGF-1、MMP-9、MMP-13 mRNA的表現量。為了更進一步研究HO-1在癌症轉移中所扮演的角色，於是我們把帶有HO-1基因的病毒拿來感染癌細胞而促使HO-1增加。由實驗結果可以得知，給予癌細胞AdHO-1處理24小時後可以使HO-1的mRNA 以及蛋白增加，但是不帶有HO-1基因的病毒對HO-1卻沒有任何影響。之後我們也觀察到HO-1過量表現可以增加癌細胞的移行能力以及IGF-1、MMP-9、MMP-13 mRNA的表現量。此外，藉由HO-1過量表現不僅可以增加MMP-13 promoter activity也可以增加其蛋白表現量。由以上的結果顯示，HO-1對於PC-3以及A549的轉移扮演著重要的角色。本結果顯示HO-1或許可以作為抗癌藥物發展的另一標的。

關鍵字

前列腺癌 ； 肺部上皮細胞癌 ； 血基質氧化酶移行 ； 入侵 ； MMP ； IGF-1

並列摘要

Heme oxygenase-1 (HO-1) is an inducible enzyme that catalyzed oxidative degradation of heme to form biliverdin, carbon monoxide (CO), and free iron. Biliverdin is subsequently reduced to bilirubin by the enzyme biliverdin reductase. Recent studies have demonstrated the important role of HO-1 in cytoprotection and diverse biological functions, however, the relation between HO-1 and cancer metastasis is not well defined. Here we upregulated HO-1 expression by hemin or using HO-1 adenovirus in PC-3 and A549 to examine the role of HO-1 in tumor cell migration or invasion. Increase of HO-1 by hemin enhanced the migration and invasion of PC-3 and A549 tumor cells. Hemin also potentiated the mRNA expression of IGF-1, MMP-9, and MMP-13. Induction of HO-1 gene in PC-3 and A549 by adenovirus also increased the expression of HO-1. Infection with 30 MOI of the HO-1 adenovirus (AdHO-1) for 24 hr enhanced the expression of HO-1 mRNA and protein, whereas, a control adenovirus lacking the HO-1 gene had no effect. Adenoviral delivery of the HO-1 to PC-3 also increased the mRNA expression of IGF-1, MMP-9, and MMP-13. Overexpression of human HO-1 gene in PC-3 increased the MMP-13 promoter activity using luciferase expression system. In addiction, the expression of MMP-13 protein was also upregulated by AdHO-1. Our results provide evidences to show the important role of HO-1 in the mediation of migration and invasion in PC-3 and A549. These results also indicated that HO-1 maybe a good target for the development of anticancer drugs.

並列關鍵字

prostate cancer ； lung cancer ； heme oxygenase ； migration ； invasion ； MMP ； IGF-1

參考文獻

Adams JC and Watt FM (1993) Regulation of development and differentiation by the extracellular matrix. Development (Cambridge, England) 117(4):1183-1198.

Agarwal A, Balla J, Alam J, Croatt AJ and Nath KA (1995) Induction of heme oxygenase in toxic renal injury: a protective role in cisplatin nephrotoxicity in the rat. Kidney international 48(4):1298-1307.

Airola K, Johansson N, Kariniemi AL, Kahari VM and Saarialho-Kere UK (1997) Human collagenase-3 is expressed in malignant squamous epithelium of the skin. The Journal of investigative dermatology 109(2):225-231.

Ala-aho R, Ahonen M, George SJ, Heikkila J, Grenman R, Kallajoki M and Kahari VM (2004) Targeted inhibition of human collagenase-3 (MMP-13) expression inhibits squamous cell carcinoma growth in vivo. Oncogene 23(30):5111-5123.

Ashworth JL, Murphy G, Rock MJ, Sherratt MJ, Shapiro SD, Shuttleworth CA and Kielty CM (1999) Fibrillin degradation by matrix metalloproteinases: implications for connective tissue remodelling. The Biochemical journal 340 ( Pt 1):171-181.