miR-100在卵巢癌中的表达及其意义
摘要
卵巢癌是常见的妇科肿瘤,其死亡率居妇科肿瘤之首。晚期卵巢癌的5年生存率仅为20%-30%。卵巢癌起病隐匿,症状只有在疾病蔓延至腹膜腔表面时才表现出来,很难在早期发现和诊断。但在这个时期,已不能通过手术清除所有病灶,导致手术后的再次复发。因此,晚期卵巢癌主要的治疗方案为化学治疗,但卵巢癌通常呈进展状态且易对化疗药物产生耐受性。所以,进一步研究卵巢癌的发病机制、寻找新的有效治疗卵巢癌的方法对治疗和手术后预防复发有非常重要的意义。MicroRNAs是近年来发现的一类在转录水平调控基因表达的、长度约为18-24个左右的核糖核酸分子,通过与靶基因的mRNA-3′UTR区域配对调控基因的表达。已证明,miRNAs能够调控多种生理学和病理学的过程,如细胞分化、细胞增殖和肿瘤形成。miRNAs可作为癌基因或抑癌基因,参与调节人类肿瘤形成的多个信号通路途径。有学者利用miRNA表达谱芯片等多种方法对卵巢肿瘤和正常女性卵巢组织的miRNAs表达进行检测,发现卵巢癌中miR-100等多种miRNAs异常表达,但目前miRNAs在卵巢癌中的具体作用机制尚未明确。我们通过RT-PCR分析九例卵巢浆液性癌和四例卵巢正常组织中miR-100的表达发现,与正常卵巢组织相比,卵巢浆液性癌中的miR-100表达下调。同时,我们发现在卵巢癌细胞株中过表达miR-100可以减低卵巢癌细胞对顺铂的耐药性,但并不影响卵巢癌细胞的生长;通过动物试验利用裸鼠在体内分析肿瘤新生血管生成,发现过表达miR-100可抑制卵巢癌的新生血管生成。为明确miR-100在卵巢癌中的作用机制,我们通过荧光素酶报告基因证明miR-100直接靶向mTOR-3′UTR并抑制其表达。我们推测miR-100对mTOR的调节可能在卵巢癌形成和新的血管生成过程中有重要的作用。这一研究结果有助于了解miR-100在卵巢癌发生中的作用,为预防和治疗卵巢癌提供理论依据。
Ovarian cancer is the most common and the leading cause of death from gynecological malignancy. The 5-year survival rate of advanced ovarian cancer is only 20%-30%. The symptoms of ovarian cancer are generally observed only after the cancer has spread to the surface of the peritoneal cavity. At this stage, it is impossible to surgically remove all apparent lesions, and this accounts for the high rate of cancer recurrence after surgery. Hence, advanced ovarian cancer is the major interest in chemoprevention research. Chemotherapy is the major strategy for the treatment of advanced ovarian cancer, but the disease of this stage usually deteriorates. The cancer cells are prone to gain the capacity of drug resistance against chemotherapeutic agents. Thus, it is very important to further explore the pathogenesis of ovarian cancer, and to find new and effective treatment of ovarian cancer for diagnosis and prevention after operation. MicroRNAs (miRNAs) are evolutionarily conserved, endogenous, small, noncoding, RNA molecules of about 22 nuleotides in length that function as post-transcriptional gene regulators. miRNAs inhibit the expression of target genes by affecting the translation or stability of target mRNA by binding to a target site in the 3′-UTR of target mRNAs. It is revealed that miRNAs regulate various physiological and pathological pathways such as cell differentiation, cell proliferation and tumoriogenesis. miRNAs may function as oncogenes or tumor suppressors, and they involved in many cell signal pathways of tumor formation. Some researcher analyzed miRNAs expression in ovarian tumors and normal ovarian tissues by hybridization of the array. They found some miRNA and miR-100 are down-regulated in ovarian tumors, but the mechanism of miRNAs in ovarian cancer is still not very clear. We analyzed miR-100 expression in 9 serous ovarian cancer tissues and 4 normal ovarian tissues by RT-PCR and proved miR-100 was down-regulated in tumors. In ovarian cancer cell lines, overexpressing miR-100 can reduce ovarian cancer cells resistant to cisplatin and inhibit ovarian cancer tumor angiogenesis in vivo, but do not change the growth of ovarian cancer. We showed miR-100 directly targeting mTOR-3′UTR and inhibited mTOR expression by luciferase assay. So we speculate that miR-100 maybe plays an important role in the ovarian cancer tumorigenesis and angiogenesis through inhibition of mTOR translation. We will further clarify the mechanisms of miR-100 in the ovarian cancer tumorigenesis and angiogenesis and build the network of signaling pathways. Our work may shed light in new strategies for ovarian tumor therapy in future.
Ovarian cancer is the most common and the leading cause of death from gynecological malignancy. The 5-year survival rate of advanced ovarian cancer is only 20%-30%. The symptoms of ovarian cancer are generally observed only after the cancer has spread to the surface of the peritoneal cavity. At this stage, it is impossible to surgically remove all apparent lesions, and this accounts for the high rate of cancer recurrence after surgery. Hence, advanced ovarian cancer is the major interest in chemoprevention research. Chemotherapy is the major strategy for the treatment of advanced ovarian cancer, but the disease of this stage usually deteriorates. The cancer cells are prone to gain the capacity of drug resistance against chemotherapeutic agents. Thus, it is very important to further explore the pathogenesis of ovarian cancer, and to find new and effective treatment of ovarian cancer for diagnosis and prevention after operation. MicroRNAs (miRNAs) are evolutionarily conserved, endogenous, small, noncoding, RNA molecules of about 22 nuleotides in length that function as post-transcriptional gene regulators. miRNAs inhibit the expression of target genes by affecting the translation or stability of target mRNA by binding to a target site in the 3′-UTR of target mRNAs. It is revealed that miRNAs regulate various physiological and pathological pathways such as cell differentiation, cell proliferation and tumoriogenesis. miRNAs may function as oncogenes or tumor suppressors, and they involved in many cell signal pathways of tumor formation. Some researcher analyzed miRNAs expression in ovarian tumors and normal ovarian tissues by hybridization of the array. They found some miRNA and miR-100 are down-regulated in ovarian tumors, but the mechanism of miRNAs in ovarian cancer is still not very clear. We analyzed miR-100 expression in 9 serous ovarian cancer tissues and 4 normal ovarian tissues by RT-PCR and proved miR-100 was down-regulated in tumors. In ovarian cancer cell lines, overexpressing miR-100 can reduce ovarian cancer cells resistant to cisplatin and inhibit ovarian cancer tumor angiogenesis in vivo, but do not change the growth of ovarian cancer. We showed miR-100 directly targeting mTOR-3′UTR and inhibited mTOR expression by luciferase assay. So we speculate that miR-100 maybe plays an important role in the ovarian cancer tumorigenesis and angiogenesis through inhibition of mTOR translation. We will further clarify the mechanisms of miR-100 in the ovarian cancer tumorigenesis and angiogenesis and build the network of signaling pathways. Our work may shed light in new strategies for ovarian tumor therapy in future.
引文
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3. Venn A, Healy D, McLachlan R. Cancer risks associated with the diagnosis of infertility. Best Pract Res Clin Obstet Gynaecol. 2003; 17(2): 343-67.
4. Gallion HH, Smith SA. Hereditary ovarian carcinoma. Semin Surg Oncol. 1994; 10(4): 249-54.
5. Grindedal EM, Renkonen-Sinisalo L, Vasen H, Evans G, Sala P, Blanco I, Gronwald J, Apold J, Eccles DM, Sánchez AA, Sampson J, J?rvinen HJ, Bertario L, Crawford GC, Stormorken AT, Maehle L, Moller P.Survival in women with MMR mutations and ovarian cancer: a multicentre study in Lynch syndrome kindreds. J Med Genet. 2010; 47(2): 99-102.
6. The National Board of Health and Welfare, Official Statistics of Sweden. Cancer incidence in Sweden. Stockholm, Sweden: Centre for Epidemiology, 1999.
7. RosanòL, Di Castro V, Spinella F, Tortora G, Nicotra MR, Natali PG, Bagnato A. Combined targeting of endothelin A receptor and epidermal growth factor receptor in ovarian cancer shows enhanced antitumor activity. Cancer Res. 2007; 67(13): 6351-9.
8. Meng Q, Xia C, Fang J, Rojanasakul Y, Jiang BH. Role of PI3K and AKT specific isoforms in ovarian cancer cell migration, invasion and proliferation through the p70S6K1 pathway. Cell Signal. 2006; 18(12): 2262-71.
9. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell,2004;116(2):281-297.
10. Lee RC, Feinbaum RL, Ambros V. The C.elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell, 1993; 75: 843-854.
11. Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE, Horvitz HR, Ruvkun G. The 21 nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature, 2000; 403(6772): 901-906.
12. Ambros V. The functions of animal microRNAs. Nature, 2004; 431(7006):350-355.
13. Lee Y, Jeon K, Lee JT, Kim S, Kim VN. MicroRNA maturation: stepwise processing and subcellular localization. EMBO J, 2002; 21(17):4663-4670.
14. Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, Bartel DP, Linsley PS, Johnson JM. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature, 2005; 433(7027):769-773.
15. Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell, 2005; 120(1):15-20.
16. Sevignani C, Calin GA, Siracusa LD, Croce CM. Mammalian microRNAs: a small world for fine-tuning gene expression. Mamm Genome, 2006; 17(3):189-202.
17. Gartel AL, Kandel ES. RNA interference in cancer. Biomol Eng, 2006; 23 (1): 17-34.
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