microRNA-107 functions as a candidate tumor-suppressor gene in head and neck squamous cell carcinoma by downregulation of protein kinase Cɛ.
microRNA-107 functions as a candidate tumor-suppressor gene in head and neck squamous cell carcinoma by downregulation of protein kinase Cɛ.
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DOI：
10.1038/onc.2011.565
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发表时间：
2012-09-06
期刊：
影响因子：
8
通讯作者：
Pan, Q.
中科院分区：
文献类型：
--
作者：
Datta, J.;Smith, A.;Lang, J. C.;Islam, M.;Dutt, D.;Teknos, T. N.;Pan, Q.
头颈部鳞状细胞癌（HNSCC）是全球第六大流行癌症，每年诊断出约60万例新病例。了解导致HNSCC的分子途径对于确定抗癌药物开发的新靶点至关重要。蛋白激酶Cε（PKCε）在HNSCC中升高，并调节Akt、Stat 3和Rho GTP酶的活化。迄今为止，HNSCC中PKCε失调的分子机制仍有待阐明。计算机模拟分析在PKCε的3 '-非翻译区（UTR）中鉴定了三个推定的microRNA-107（miR-107）结合位点。在HNSCC细胞系中，miR-107和PKCε之间显示出负相关。miR-107的递送降低了SCC 15、SCC 25和CAL 27（具有高PKCε和低miR-107的三种HNSCC细胞系）中的PKCε水平。含有PKCε的3 '-UTR的荧光素酶报告基因构建体的活性被miR-107下调，并且三个同源miR-107结合位点中的突变完全消除了miR-107的调节。用miR-107处理显著阻断SCC 25和CAL 27细胞中的细胞增殖、DNA复制、集落形成和侵袭。miR耐药PKCε的异位表达足以部分挽救miR-107过表达SCC 25细胞中的功能丧失表型。与CAL 27/miR-对照细胞相比，CAL 27/miR-107细胞中裸鼠中的肿瘤生长延迟93 ± 7%。最后，具有升高的PKCε的人原发性HNSCC肿瘤具有降低的miR-107表达。我们的研究结果表明，PKCε直接受miR-107的调节，而且，提示miR-107可能是HNSCC的潜在抗癌治疗剂。
Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide with about 600,000 new cases diagnosed each year. Understanding the molecular pathways that lead to HNSCC is crucial to identify new targets for anti-cancer drug development. Protein kinase Cε (PKCε) is elevated in HNSCC and regulates the activation of Akt, Stat3, and Rho GTPases. To date, the molecular mechanism of PKCε dysregulation in HNSCC remains to be elucidated. In silico analysis identified three putative microRNA-107 (miR-107) binding sites in the 3'-untranslated region (UTR) of PKCε. An inverse relationship was revealed between miR-107 and PKCε in HNSCC cell lines. Delivery of miR-107 reduced PKCε levels in SCC15, SCC25, and CAL27, three HNSCC cell lines with high PKCε and low miR-107. The activity of a luciferase reporter construct containing the 3'-UTR of PKCε was down-regulated by miR-107 and mutations in the three cognate miR-107 binding sites completely ablated the regulation by miR-107. Treatment with miR-107 significantly blocked cell proliferation, DNA replication, colony formation, and invasion in SCC25 and CAL27 cells. Ectopic expression of miR-resistant PKCε was sufficient to partially rescue the loss-of-function phenotype in miR-107-overexpressing SCC25 cells. Tumor growth in nude mice was retarded by 93 ± 7% in CAL27/miR-107 cells compared to CAL27/miR-control cells. Lastly, human primary HNSCC tumors with elevated PKCε had reduced miR-107 expression. Our results demonstrate that PKCε is directly regulated by miR-107 and moreover, suggest that miR-107 may be a potential anti-cancer therapeutic for HNSCC.
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DOI：
10.1158/1078-0432.ccr-08-3131
发表时间：
2009-04-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Avissar M;Christensen BC;Kelsey KT;Marsit CJ
通讯作者：
Marsit CJ
DOI：
10.1016/0360-3016(92)90642-u
发表时间：
1992-01-01
影响因子：
7
作者：
LARAMORE, GE;SCOTT, CB;CAMPBELL, BH
通讯作者：
CAMPBELL, BH
影响因子：
11.2
作者：
Kozaki, Ken-ichi;Imoto, Issei;Inazawa, Johji
通讯作者：
Inazawa, Johji
影响因子：
3.6
作者：
Lee, Kwang-Hyuck;Lotterman, Craig;Maitra, Anirban
通讯作者：
Maitra, Anirban
影响因子：
9.7
作者：
Liu, Xiqiang;Jiang, Lu;Wang, Anxun;Yu, Jinsheng;Shi, Fei;Zhou, Xiaofeng
通讯作者：
Zhou, Xiaofeng