猴病毒40型T/t-common蛋白質在HER-2/neu大量表現癌細胞中增強etoposide或放射線所引起細胞凋亡之研究

Enhancement of Etoposide- or Irradiation-Induced Apoptosis in HER-2/neu-overexpressing Cancer Cells by Simian Virus 40 T/t-common Polypeptide

郭周樺(Chou-Hua Kuo)

指導教授 ： 王萬波

國立臺灣大學/醫學院/微生物學研究所/碩士(2005年)

https://doi.org/10.6342/NTU.2005.02032

摘要

HER-2/neu 屬於表皮生長因子接受器家族 (epidermal growth factor receptor family；EGF receptor family)的一員。許多的癌症中，常常會發現 HER-2/neu 原致癌基因有大量表現的現象，這些癌症包含了卵巢癌、乳癌、肺癌、腎癌、結腸癌、胃癌等，HER-2/neu大量表現會增加腫瘤轉移的機率，提高化療抗藥性和增強腫瘤的血管新生等。研究發現，抑制 HER-2/neu 基因的表現可以抑制 HER-2/neu 大量表現的癌細胞的腫瘤形成能力，因此 HER-2/neu 基因可能是癌症治療上一個非常好的標的。
我們實驗室之前證實SV40大T 和小t抗原所共有的氨基端區域T/t-common，會專一性的抑制 HER-2/neu 基因的promoter，並且可以抑制HER-2/neu大量表現的癌細胞株(SK-OV-3)內HER-2/neu 基因的表現，進而達到抑制SK-OV-3的腫瘤形成能力(Lin et al., 2000)。另外，我們也發現T/t-common透過誘導癌細胞的細胞凋亡(apoptosis)達成腫瘤抑制能力，T/t-common只會專一地誘導HER-2/neu大量表現的癌細胞的凋亡，但不會引發HER-2/neu低量表現的癌細胞及正常細胞的凋亡。
放射線治療及化學治療是兩種最常見的癌症治療方式，但是過高的劑量常常會造成噁心、嘔吐、掉頭髮、體內白血球數下降而易於細菌感染等副作用。另外，化療抗藥性也常常發生在持續治療的癌症病患中。鑒於實驗室先前的研究，我們想探討 T/t-common 是否可藉由與其他抗癌藥物的混合治療，來達到降低對HER-2/neu大量表現的癌細胞投予之抗癌藥物的劑量，並探討混合治療造成HER-2/neu大量表現的癌細胞死亡的機制，結果發現，T/t-common會使HER-2/neu大量表現的癌細胞對抗癌藥物etopposide及放射線更具感受性並使其走向細胞凋亡，但是這種更具感受性的現象在HER-2/neu低量表現的癌細胞中並不會出現。

關鍵字

猴病毒40型 ； HER-2/neu大量表現

並列摘要

HER-2/neu proto-oncogene belongs to epidermal growth factor receptor families. Overexpression or gene amplification of HER-2/neu has been detected frequently in many types of human cancers, including cancers of breast, ovary, lung, kidney, colon, bladder, stomach and salivary gland. Overexpression of HER-2/neu enhances metastatic potential, chemoresistance and tumor angiogenesis. Previous studies showed that inhibition of HER-2/neu gene expression leads to suppression of tumorigenicity of HER-2/neu-overexpressing cancer cells. Therefore, HER-2/neu gene represents a suitable target for cancer therapy.
Our lab previously reported that T/t-common, which contains the N-terminal common domain of simian virus 40 large T and small t antigens, can specifically repress the HER-2/neu promoter and its expression in HER-2/neu-overexpressing ovarian carcinoma SK-OV-3 cells. This phenomenon may presumably contribute to T/t-common suppression of the tumorigenic potential of these cancer cells. Furthermore, we discovered that the ability of T/t-common to suppress the tumorigenic potential of HER-2/neu-overexpressing cells is through induction of apoptosis. T/t-common specifically induces apoptosis in HER-2/neu-overexpressing cells but not in HER-2/neu low-expressing or non-transformed cells.
Radiotherapy and chemotherapy are most common ways to treat cancer, but the overdose of drugs usually causes severe side effects such as vomits, alopecia, leucopenia, and susceptible to bacterial infections. In addition, chemoresistances often occurred during the prolonged period of treatment. Therefore, based on previous studies in our lab, we further investigated the possibilities of combination therapy using T/t-common and chemotherapeutic agents or irradiation in treatment of HER-2/neu-overexpressing cancers. Our data indicate that T/t-common can specifically enhance cell death induced by either etoposide or irradiation in HER-2/neu-overexpressing breast cancer cells SK-OV-3 and AU565 but not in HER-2/neu low-expressing breast cancer cells MDA-MB-231 and laryngeal cancer cells HEp-2. Further, this sensitization of HER-2/neu-overexpressing cancer cells to etoposide or irradiation is through the induction of apoptosis.

並列關鍵字

SV40 ； HER-2/neu-overexpressing

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