中国解放军总医院（301医院）韩卫东教授和来自美国凯斯西储大学的研究人员，在国际癌症研究领域著名期刊《Clinical Cancer Research》发表题为“Genetic and methylation-induced loss of miR-181a2/181b2 within chr9q33.3 facilitate tumor growth of cervical cancer through pIK3R3/Akt/FoxO signaling pathway”的研究论文。这项研究探讨了miR-181a2/181b2在宫颈癌中所发挥的抑癌作用，并为宫颈癌的治疗指出了新的途径。点击阅读韩卫东教授相关研究：Jpathol：应用ExiqonmicroRNA芯片研究结直肠癌。

宫颈癌是全球女性癌症死亡的第四大原因，在中国每年有近150000例新诊断的病例。人乳头瘤病毒（HpV）感染是宫颈癌的主要环境危险因素，其不同预后结果表明，重要的遗传危险因素参与了宫颈癌的进展。对受感染的278对同胞的全基因组扫描，已将chr9q31-33区确定为宫颈癌的易感基因位点，而这个区域的肿瘤抑制作用已在多种人类癌症中得以证明。

值得注意的是，有研究在15-30%的宫颈癌中发现了LOH（杂合性丢失）。虽然在这一区域检测到了几个候选的免疫相关或是肿瘤抑制基因，如DEC1、ENG和TSCOT，但是，这个区域与人类肿瘤之间的分子联系，仍没有得到充分的理解。这个区域在癌症的分子发病机理中的作用，似乎可能有一种替代机制。

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虽然曾经被认为是转录“噪音”，转录后调节因子microRNAs（miRNAs）目前被公认为在宫颈癌的发病机制中有重要作用，如miR-21，133B，138等。特别感兴趣的是，因为超过50%的miRNA位于脆性位点和癌症相关的染色体异常区域，因此，中断点相关的miRNA可能有助于我们深入考虑脆性位点在癌症发展中的因果作用。例如，Chr19q13.4异常可能导致C19MC簇的miRNAs的表达，这可能与甲状腺腺瘤发生有因果关系。阐明“伴随着chr9q31-33区域缺失而出现的miRNA干扰，是否可以解释宫颈癌的关键分子致病机制”，是非常重要的。

miR-181a-2（miR -181a2）和miR -181b-2（miR -181b2）位于缺失的chr9q31-33区域，属于miR-181家族。四个高度保守的成熟miRNA成员——miR-181a、18b、181c和181d，分别来自位于三条不同染色体上的六个前体细胞：miR-181a-1和miR -181b-1在染色体1p32.1上，miR-181a-2和miR-181b-2位于染色体9q33.3上，miR-181c和miR-181d位于染色体19p13.12上。最近新兴的数据表明，miR-181家族在一些肿瘤中是解除控制的，并在癌症进展中扮演着重要的角色。

在本研究中，研究人员发现，由于基因组位点的LOH和启动子甲基化，miR-181a2/181b2在chr9q33中的表达明显减少。研究人员进一步表征了miR-181a2/181b2在体内外的肿瘤抑制作用，并证实miR-181a2/181b2损耗和宫颈癌的不良预后之间有着一定的相关性。重要的是，miR-181a2/181b2通过其靶标p55γ和随后的pI3K/AKT信号调解，发挥其抑制肿瘤的作用，从而指出了其在宫颈癌治疗中的潜在应用。

（生物通：王英）

生物通推荐原文摘要：
Genetic and methylation-induced loss of miR-181a2/181b2 within chr9q33.3 facilitate tumor growth of cervical cancer through pIK3R3/Akt/FoxO signaling pathway.
Abstract
pURpOSE:
Loss of Chr9q31-33 is one of the most common chromosome imbalances of cervical cancer, but the underlying mechanism has not been well documented.

EXpERIMENTAL DESIGN:
The loss of heterozygosity (LOH) status of Chr9q31-33 was investigated utilizing 26 microsatellite markers. We detected the expression of miR-181a2/181b2 by qRT-pCR analysis of cervical cancer cell lines and 100 paired tumor samples and corresponding adjacent non-tumor tissues. Kaplan-Meier and Cox proportional hazard regression analysis were performed to identify the prognostic value of miR-181a2/181b2. Regulation of expression was analyzed by methylation-specific pCR. The tumor suppressing effects of miR-181a2/181b2 were determined in vitro and in vivo The target gene and signaling pathway mediated the function of miR-181a2/181b2 were also identified.

RESULTS:
Chr9q33.3 was identified as one of the most deleted regions in cervical cancer. Under-expression of miR-181a2/181b2 was detected in 46% of cervical caner, and was induced by LOH of chr9q33.3 and promoter hypermethylation. Attenuated miR-181a2/181b2 expression predicted a poor prognostic phenotype and advanced clinical stage of cervical cancer. miR-181a2/181b2 prominently dampened cell cycle progression, suppressed cell growth and promoted apoptosis of tumor cells in vitro They also effectively impeded tumor formation and growth in vivo miR-181a2/181b2 exert the tumor suppressor ability by depressing direct target pIK3R3 (p55γ) and consequently modulating pIK3R3/Akt/FoxO signaling pathway.

CONCLUSIONS:
We demonstrated a cause-and-effect event beginning from loss of chr9q33.3, a frequent event in cervical cancer, to the under-expression of miR-181a2/181b2, leading to the elevated activation of pI3K pathway.