MiR-422a promotes loco-regional recurrence by targeting NT5E/CD73 in head and neck squamous cell carcinoma.
MiR-422a promotes loco-regional recurrence by targeting NT5E/CD73 in head and neck squamous cell carcinoma.
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DOI：
10.18632/oncotarget.9829
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发表时间：
2016-07-12
期刊：
影响因子：
--
通讯作者：
Poncet D
中科院分区：
文献类型：
--
作者：
Bonnin N;Armandy E;Carras J;Ferrandon S;Battiston-Montagne P;Aubry M;Guihard S;Meyronet D;Foy JP;Saintigny P;Ledrappier S;Jung A;Rimokh R;Rodriguez-Lafrasse C;Poncet D
在诊断时，60%的头颈部鳞状细胞癌（HNSCC）患者的肿瘤处于疾病的晚期（III-IV），80%的患者会在治疗后的前两年内复发，这是由于他们频繁的放射（化疗）抵抗。为了鉴定新的分子靶点和伴随生物标志物，我们研究了75例治疗后两年内无复发（R）或局部复发（无应答者，NR）的III-IV期口咽肿瘤的miRNome。有趣的是，miR-422 a在NR肿瘤中显著下调，与体外miR-422 a抑制诱导的细胞增殖和粘附增加一致。此外，我们确定了CD 73/NT 5E癌基因为miR-422 a的靶基因。事实上，miR-422 a的内源性水平的调节相反地影响CD 73的表达和酶活性。此外，敲低CD 73模拟miR-422 a上调的作用。重要的是，在肿瘤中，miR-422 a和CD 73表达水平呈负相关，并且在晚期口咽或HNSCC（N=255）肿瘤的体外两个独立队列中，二者均预测无复发生存期-特别是考虑局部（区域）复发。总之，我们首次报道了miR-422 a及其靶点CD 73参与HNSCC肿瘤的早期局部（区域）复发，并且是个性化药物的新靶点。
At the time of diagnosis, 60% of patients with head and neck squamous cell carcinoma (HNSCC) present tumors in an advanced stage (III-IV) of disease and 80% will relapse within the first two years post-treatment, due to their frequent radio(chemo)resistance. To identify new molecular targets and companion biomarkers, we have investigated the miRNome of 75 stage III-IV oropharynx tumors without relapse (R) or with loco-regional relapse (non-responder, NR) within two years post-treatment. Interestingly, miR-422a was significantly downregulated in NR tumors, in agreement with the increase in cell proliferation and adhesion induced by miR-422a inhibition in vitro. Furthermore, we identified CD73/NT5E oncogene as target of miR-422a. Indeed, modulation of the endogenous level of miR-422a inversely influences the expression and the enzymatic activity of CD73. Moreover, knocking down CD73 mimics the effects of miR-422a upregulation. Importantly, in tumors, miR-422a and CD73 expression levels are inversely correlated, and both are predictive of relapse free survival - especially considering loco(regional) recurrence - in vitro two independent cohorts of advanced oropharynx or HNSCC (N=255) tumors. In all, we reported, for the first time, that MiR-422a and its target CD73 are involved in early loco(regional) recurrence of HNSCC tumors and are new targets for personalized medicine.
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