近日,，來自美國俄亥俄州立大學(xué)的研究人員發(fā)現(xiàn),，在頭頸部鱗狀細胞癌（HNSCC）細胞內(nèi)，MicroRNA-34a的表達失調(diào)會促進了腫瘤的生長及腫瘤血管的生成,，則控制miR-34a的活性也許能夠成為新的策略來治療HNSCC,。相關(guān)研究成果于5月22日在線發(fā)表在PLoS ONE上。
MicroRNAs (miRs)是小的非編碼RNA,，在癌癥發(fā)生過程中扮演了重要角色,，研究發(fā)現(xiàn)，它們能夠作為癌基因促進癌癥發(fā)生,，也能夠作為腫瘤抑制因子阻遏腫瘤的生成,。miR-34a是一種腫瘤抑制因子，在一系列腫瘤類型中都被發(fā)現(xiàn)表達下調(diào),。然而,，miR-34a對頭頸部鱗狀細胞癌(HNSCC）作用機制目前還不明確。
在這項研究里,，研究人員發(fā)現(xiàn),，將miR-34a異位表達到HNSCC細胞系，能夠顯著的抑制腫瘤細胞的增生,、集落形成以及細胞遷移,。而且,，過表達miR-34a也能夠顯著的下調(diào)E2F3以及生存素的水平。進一步研究發(fā)現(xiàn),，miR-34a介導(dǎo)的對細胞增生及集落形成的抑制作用,，主要是通過E2F3a所介導(dǎo)。除此以外,，對來自HNSCC患者的腫瘤樣品的研究表明,，miR-34a與生存素以及miR-34a與E2F3水平都表現(xiàn)出一個反相關(guān)的關(guān)系。
研究發(fā)現(xiàn),，在表達有miR-34a的細胞,，E2F3a的過表達能夠完全恢復(fù)生存素的表達水平，這表明miR-34a可能通過E2F3a調(diào)節(jié)了生存素的表達,。在一個嚴重聯(lián)合免疫缺陷（SCID）小鼠異種移植模型中,，研究者還發(fā)現(xiàn)，miR-34a的異位表達也能夠顯著的抑制腫瘤的生長以及腫瘤血管生成,。有趣的是,，他們發(fā)現(xiàn)miR-34a是通過阻礙腫瘤細胞產(chǎn)生VEGF以及直接抑制內(nèi)皮細胞的功能，來抑制腫瘤血管的生成,。
該研究闡明了頭頸部鱗狀細胞癌(HNSCC）細胞內(nèi)miR-34a的作用機制,，Pawan Kumar表示，靶向一個miR-34a也許能夠成為新的HNSCC治療策略,。（生物谷Deepblue編譯）
doi: 10.1371/journal.pone.00376
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PMID:
Dysregulation of MicroRNA-34a Expression in Head and Neck Squamous Cell Carcinoma Promotes Tumor Growth and Tumor Angiogenesis
Bhavna Kumar, Arti Yadav, James Lang, Theodoros N. Teknos, Pawan Kumar.
MicroRNAs (miRs) are small non-coding RNAs that play an important role in cancer development where they can act as oncogenes or as tumor-suppressors. miR-34a is a tumor-suppressor that is frequently downregulated in a number of tumor types. However, little is known about the role of miR-34a in head and neck squamous cell carcinoma (HNSCC).Ectopic expression of miR-34a in HNSCC cell lines significantly inhibited tumor cell proliferation, colony formation and migration. miR-34a overexpression also markedly downregulated E2F3 and survivin levels. Rescue experiments using microRNA resistant E2F3 isoforms suggest that miR-34a-mediated inhibition of cell proliferation and colony formation is predominantly mediated by E2F3a isoform. In addition, tumor samples from HNSCC patients showed an inverse relationship between miR-34a and survivin as well as miR-34a and E2F3 levels.Overexpression of E2F3a completely rescued survivin expression in miR-34a expressing cells, thereby suggesting that miR-34a may be regulating survivin expression via E2F3a. Ectopic expression of miR-34a also significantly inhibited tumor growth and tumor angiogenesis in a SCID mouse xenograft model. Interestingly, miR-34a inhibited tumor angiogenesis by blocking VEGF production by tumor cells as well as directly inhibiting endothelial cell functions.Taken together, these findings suggest that dysregulation of miR-34a expression is common in HNSCC and modulation of miR34a activity might represent a novel therapeutic strategy for the treatment of HNSCC.
