中國醫藥大學機構典藏 China Medical University Repository, Taiwan:Item 310903500/46198
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    Please use this identifier to cite or link to this item: http://ir.cmu.edu.tw/ir/handle/310903500/46198


    Title: DDB2負調控作用參與Lapatinib誘發癌細胞對化學治療產生交叉抗性之探討
    Involvement of DDB2 Down-regulation in Lapatinib-induced Cross-resistance to Chemotherapy
    Authors: 何宥豪;He, Yu-Hao
    Contributors: 癌症生物學研究所碩士班
    Keywords: 交叉抗性;化學治療;乳癌;拉帕替尼;Cross-resistance;Chemotherapy;Breast cancer;Lapatinib
    Date: 2012-07-30
    Issue Date: 2012-08-31 16:34:36 (UTC+8)
    Publisher: 中國醫藥大學
    Abstract: ErbB2 (HER2) 過度表現約占整體乳癌的20-30%，並且調控許多癌化過程，包含腫瘤增生、抗細胞凋亡、以及腫瘤轉移。Lapatinib 是一種ErbB2 與EGFR 酪胺酸激酶的雙重抑制劑，主要為對抗ErbB2 的口服標靶治療藥物，臨床上能夠提高ErbB2 陽性乳癌病患的存活率。不幸的是lapatinib 治療會快速地失去效力，乳癌病患服藥約一年即對此藥物產生抗藥性，其形成機制已廣泛被探討。然而，目前仍不清楚對於lapatinib 產生抗藥性之後，是否亦改變對化學治療或放射線治療的敏感性，以及其中的分子機制。我們的研究結果顯示，長期給予lapatinib 後，均使得ErbB2 陽性以及陰性的乳癌細胞株對paclitaxel、vinorelbine、carboplatin、以及X-ray 產生交叉抗性，但對於5-Fluorouracil 以及doxorubicin 則無此現象。進一步研究發現，DDB2 (Damaged DNA-Binding Protein 2) 表現降低可能與此交叉抗性之形成相關，DDB2 可結合至受損的DNA 並參與DNA 修復以及調控細胞凋亡。我們發現在各種lapatinib 抗藥細胞株中，DDB2 表現均明顯降低，另外大量表現DDB2 可回復lapatinib 抗藥細胞株對carboplatin 的敏感性，但對anti-mitotic drugs 則無此作用，顯示lapatinib 可能透過降低DDB2 表現而使癌細胞對Carboplatin 產生交叉抗性。我們亦發現，lapatinib 抗藥細胞株的DDB2 表現下降伴隨著p53 以及lincRNA-p21 之表現增加，以shRNA或siRNA 抑制p53 表現則回復DDB2 的蛋白表現量。這些結果顯示lapatinib 可能藉由活化p53/lincRNA-p21路徑而抑制DDB2 的表現，進而降低lapatinib 抗藥細胞株對於carboplatin 的敏感性。除此之外，我們也發現B 型肝炎病毒X 蛋白的大量表現，可能透過活化IKKα進而抑制DDB2 蛋白表現，可能與B 型肝炎病毒引發化學治療抗性相關。因此，癌細胞面對各種環境因素可藉由不同訊息傳遞路徑而共同負調控DDB2的表現，藉此引起化療抗性。這些研究成果有助於了解lapatinib 抗藥細胞如何對化學療法產生交叉抗性，對臨床上不同階段的用藥選擇亦可能有所助益。 然而，未來仍需要更多研究來探討其中的分子機制，期望能有助於增加化學療法的臨床療效。
    ErbB2 has been shown to be overexpressed in 20-30% of breast cancer cells, and activation of ErbB2 transduces several oncogenic pathways involved in tumor proliferation, anti-apoptosis, and metastasis. Targeted therapies against ErbB2, such as lapatinib, an ErbB2/EGFR dual tyrosine kinase inhibitor (TKI), were thereby developed and showed clinical benefits to improve the survival rate of patients with advanced ErbB2-positive breast cancers. Unfortunately, the therapeutic efficacy of lapatinib is eventually limited due to the rapid formation of acquired resistance within
    1 year of treatment. Although the molecular mechanisms underlying lapatinib resistance have been widely investigated, it is unknown whether and how lapatinib treatment causes cross-resistance to chemotherapy and radiotherapy, the remaining therapeutic options for the lapatinib-resistant patients. In our study, we found that acquired resistance to lapatinib rendered both ErbB2-positive and -negative cancer cells more resistant to paclitaxel, vinorelbine, carboplatin, and X-ray, but not 5-Fluorouracil or doxorubicin in comparison with their parental cells. Our data further showed that Lap clone cells (Lapatinib resistant cancer cell lines) expressed lower level of damaged DNA-binding protein 2 (DDB2), which binds to damaged DNA and plays a critical role in regulating DNA repair and cell apoptosis, in comparison with their parental counterparts. Restoration of DDB2 expression can re-sensitize Lap clone cells to carboplatin but not paclitaxel and vinorelbine, suggesting that lapatinib may insensitize cancer cells to carboplatin by down-regulating DDB2. Accompanying with DDB2 down-regulation, p53/lincRNA-p21 axis was up-regulated in Lap clone cells. De-repression of DDB2 expression by silencing p53 further suggests the involvement of p53/lincRNA-p21 in lapatinib-elicited DDB2 down-regulation and cross chemoresistance. In addition to lapatinib resistance, our data further revealed that overexpression of hepatitis B viral-encoded x protein (HBx) may also contribute to chemoresistance by suppressing DDB2 expression in an IKK-dependent manner. These findings suggest that DDB2 down-regulation through different mechanisms, including p53/lincRNA-p21 axis and IKK, may be a common and critical event contributing to chemoresistance in response to various stimuli. Although further studies are required to address the detailed molecular mechanisms, our data provides
    new insight into lapatinib-induced chemoresistance, and will also be helpful to develop new strategies to overcome the cross-resistance between lapatinib and chemotherapy.
    Appears in Collections:[Graduate Institute of Cancer Biology] Theses & dissertations

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