TMEM102作為上皮性卵巢癌的預後指標與化學治療抗性的研究

Abstract

根據衛生福利部2019癌症登記報告，上皮性卵巢癌的年齡標準化發生率為每十萬名女性9.16人，居女性癌症發生率第七位，並有逐年增加及疾病年輕化的趨勢。超過百分之七十的卵巢癌病人在被診療時已是晚期。卵巢癌治療包括減積手術及輔助化學治療；即使接受化學治療，復發率仍高達50-70%；許多腫瘤細胞產生化學治療抗藥性造成疾病進展或腫瘤轉移。針對腫瘤血管新生的標靶藥物作為合併化學治療的維持治療，不論是在初次治療或復發的卵巢癌均顯示能改善無病存活率。針對基因修復機制的多聚ADP 核醣聚合酶抑制劑在具有BRCA基因突變及基因同源重組缺陷的卵巢癌病人及腫瘤細胞，更是顯著延長存活率。近期的臨床試驗進一步發現，相較於單一藥物，合併上述兩種藥物進一步增加卵巢癌治療的反應率。 目前除了上述臨床較常使用的標靶藥物，其他許多針對不同分子 (PI3K, mTOR，MAPK pathway，HER2，PDGF，folate receptor和賀爾蒙受器等) 的標靶藥物也在開發中。免疫治療在許多癌症已廣為研究和應用。在卵巢癌也發現腫瘤內的淋巴細胞數目和存活率有正相關，卵巢癌細胞也具有許多腫瘤相關抗原能引發專一性的免疫反應。隨著對卵巢癌及腫瘤微環境的了解，包括調節T細胞、浸潤的骨髓來源抑制性細胞及其所分泌的細胞激素等，為卵巢癌的免疫治療給予新的研究方向。針對免疫檢查點的抑制劑是近期研究的焦點；免疫治療合併化學治療藥物、多聚ADP 核醣聚合酶抑制劑、小分子抑制劑及放射治療是未來可能的治療策略。 在本研究中我們發現TMEM102 可以作為上皮性卵巢癌病患的預後指標。我們共分析226個卵巢癌病患，發現晚期患者或具有化學治療抗藥性者有顯著較高的TMEM102基因表現。TMEM102基因表現較高的患者無病存活期與整體存活期顯著較短。對於卵巢癌細胞施予細胞毒性藥物並進行實驗分析，TMEM102基因表現較高的細胞在經細胞毒性藥物處置後的細胞凋亡數目顯著較低。TMEM102基因可藉由提高熱休克蛋白及存活素的表現，減少細胞色素c及caspase 9蛋白酶，進而抑制紫杉醇引起的卵巢癌細胞凋亡。這些結果顯示TMEM102基因藉由調控粒線體路徑而造成卵巢癌細胞的抗藥性。

Ovarian cancer ranked seventh among women cancers in 2019 annual report of Taiwan Cancer Registry with an age-adjusted incidence rate of 9.16 per 100,000 women. Increasing incidence and decreasing age at diagnosis were noted in population-based registry in Taiwan. Over 70% of patients are at an advanced stage when diagnosed with ovarian cancer. The main treatments include surgery and adjuvant platinum-based chemotherapy and/or target therapy; despite all that 50-70% of patients relapse with metastasis and develop resistance to chemotherapy, at which time treatment options become limited. Anti-angiogenesis maintenance treatment improved survival in both first-line or subsequent therapy for advanced and recurrent ovarian cancer. Targeting DNA repair mechanism, poly (ADP-ribose) polymerase (PARP) inhibitors demonstrated dramatic survival benefit in patients with DNA repair defects such as homologous recombination deficiency. Recent trials showed dual maintenance therapy with VEGF inhibitors and PARP inhibitors significantly improved progression-free survival compared with single-agent. Besides anti-angiogenesis agents and PARP inhibitors, strategies targeting PI3K, mTOR, MAPK signaling pathways, HER2, PDGF, folate receptor and hormone receptors are shown to improved therapeutic effect and trials are underway. Immunotherapy is another new approach applied to a wide variety of solid tumors. The positive correlation between survival and tumor infiltrating CD8+ T cells is compelling evidence that anti-tumor immune surveillance affects outcomes in ovarian cancer. Ovarian cancer cells also express immunogenic tumor-associated antigens which elicit specific immune responses. Recent advances in understanding of ovarian cancer immunopathogenesis and tumor microenvironment, including the role of regulatory T cell, myeloid cells and immune co-signaling; help identify potential effective immunotherapy approaches for ovarian cancer. Checkpoint blockade with antibodies targeting PD-1, PD-L1/2 have emerged as promising therapies and demonstrated durable antitumor activity. Combined treatment modalities including immunotherapy, cytotoxic agents, PARP inhibitors, small molecule inhibitors and radiotherapy are proposed for their synergistic effect. In this study, we propose transmembrane protein 102 (TMEM102) as a prognostic biomarker for patients with epithelial ovarian carcinoma (EOC). We investigated the correlation between TMEM102 expression and clinical outcomes in 226 women with EOC. We also performed in vitro studies to explore the possible involvement of TMEM102 in chemoresistance. We found higher TMEM102 expression in patients with advanced stage disease, chemoresistance and a shorter progression free survival. In vitro studies showed that reduction of TMEM102 expression by small interfering RNA induced ovarian cancer cell apoptosis after cytotoxic treatment. TMEM102 up-regulated the expression of heat shock proteins and survivin, resulting in decreased cytochrome c in the mitochondria and decreased caspase 9 expression. These results suggest that TMEM102 may promote chemoresistance via inhibition of drug-induced apoptosis through mitochondrial pathway.