Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
Clin Cancer Res. 2013 Apr 15;19(8):2154-62. doi: 10.1158/1078-0432.CCR-12-3572. Epub 2013 Mar 4.
Deregulation of miRNAs is associated with almost all human malignancies. Human papillomavirus (HPV)-associated oropharyngeal carcinoma (OPC) has a significantly more favorable outcome compared with HPV-negative OPCs; however, the underlying mechanisms are not well understood. Hence, the objectives of this study were to determine whether miRNA expression differed as a function of HPV status and to assess whether such miRNAs provide prognostic value beyond HPV status.
Global miRNA profilings were conducted on 88 formalin-fixed and paraffin-embedded (FFPE) OPC biopsies (p16-positive: 56; p16-negative: 32), wherein the expression levels of 365 miRNAs plus 3 endogenous controls were simultaneously measured using quantitative real-time (qRT)-PCR. Seven FFPE specimens of histologically normal tonsils were used as controls.
Overall, 224 miRNAs were expressed in more than 80% of the investigated samples, with 128 (57%) being significantly differentially expressed between tumor versus normal tissues (P < 0.05). Upregulated miR-20b, miR-9, and miR-9* were significantly associated with HPV/p16-status. Three miRNA sets were significantly associated with overall survival (miR-107, miR-151, miR-492; P = 0.0002), disease-free survival (miR-20b, miR-107, miR-151, miR-182, miR-361; P = 0.0001), and distant metastasis (miR-151, miR-152, miR-324-5p, miR-361, miR492; P = 0.0087), which retained significance even after adjusting for p16 status. The associated biologic functions of these miRNAs include immune surveillance, treatment resistance, invasion, and metastasis.
We have identified several miRNAs, which associate with HPV status in OPC; furthermore, three candidate prognostic sets of miRNAs seem to correlate with clinical outcome, independent of p16 status. Furthermore, evaluations will offer biologic insights into the mechanisms underlying the differences between HPV-positive versus HPV-negative OPC.
miRNA 的失调与几乎所有人类恶性肿瘤都有关。与 HPV 阴性的口咽癌（OPC）相比，人乳头瘤病毒（HPV）相关的 OPC 具有显著更好的预后；然而，其潜在机制尚不清楚。因此，本研究的目的是确定 miRNA 的表达是否因 HPV 状态而异，并评估这些 miRNA 是否提供 HPV 状态以外的预后价值。
对 88 例福尔马林固定和石蜡包埋（FFPE）的 OPC 活检标本（p16 阳性：56 例；p16 阴性：32 例）进行了全局 miRNA 分析，使用定量实时（qRT）-PCR 同时测量了 365 种 miRNA 和 3 种内源性对照物的表达水平。7 例组织学正常的扁桃体 FFPE 标本用作对照。
总体而言，在 80%以上的研究样本中表达了 224 种 miRNA，其中 128 种（57%）在肿瘤与正常组织之间的表达存在显著差异（P<0.05）。上调的 miR-20b、miR-9 和 miR-9*与 HPV/p16 状态显著相关。三个 miRNA 集与总生存期（miR-107、miR-151、miR-492；P=0.0002）、无病生存期（miR-20b、miR-107、miR-151、miR-182、miR-361；P=0.0001）和远处转移（miR-151、miR-152、miR-324-5p、miR-361、miR492；P=0.0087）显著相关，即使在调整 p16 状态后，这些 miRNA 仍然具有统计学意义。这些 miRNA 的相关生物学功能包括免疫监视、治疗抵抗、侵袭和转移。
我们已经确定了几种与 OPC 中的 HPV 状态相关的 miRNA；此外，三个候选的 miRNA 预后集似乎与临床结局相关，与 p16 状态无关。此外，评估将提供对 HPV 阳性与 HPV 阴性 OPC 之间差异的潜在机制的生物学见解。
