DGCR8 is essential for tumor progression following PTEN loss in the prostate
DGCR8 is essential for tumor progression following PTEN loss in the prostate
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DOI：
10.15252/embr.201439925
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发表时间：
2015-09
期刊：
影响因子：
7.7
通讯作者：
C. Belair;Alireza Paikari;F. Moltzahn;A. Shenoy;C. Yau;M. Dall’Era;J. Simko;C. Benz;R. Blelloch
中科院分区：
文献类型：
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作者：
C. Belair;Alireza Paikari;F. Moltzahn;A. Shenoy;C. Yau;M. Dall’Era;J. Simko;C. Benz;R. Blelloch
在人类前列腺癌中，微rna生物发生机制随着前列腺癌的进展而增加。本研究表明，在Pten基因敲除的前列腺癌小鼠模型中，Dgcr8基因（该复合物的关键成分）的缺失抑制了肿瘤的进展。早期肿瘤发展未受影响，但进展到晚期前列腺上皮内瘤变受到严重抑制。Dgcr8缺失阻断了Pten诱导的基底样细胞室的扩张，而不是管腔细胞室的扩张。此外，尽管Pten敲除晚期肿瘤表现出衰老相关的β -半乳糖苷酶活性降低和增殖增加，但Dgcr8的同时缺失阻止了这些变化，导致其水平与野生型相似。分离上皮细胞中的小rna测序揭示了与PTEN丢失相关的许多miRNA变化。与Pten-Dgcr8关联一致，对人类前列腺肿瘤的大量队列分析显示Akt激活与Dgcr8 mRNA水平升高之间存在很强的相关性。总之，这些发现揭示了microrna在增强增殖和使基底细胞室扩张与Pten缺失后肿瘤进展相关中的关键作用。
In human prostate cancer, the microRNA biogenesis machinery increases with prostate cancer progression. Here, we show that deletion of the Dgcr8 gene, a critical component of this complex, inhibits tumor progression in a Pten‐knockout mouse model of prostate cancer. Early stages of tumor development were unaffected, but progression to advanced prostatic intraepithelial neoplasia was severely inhibited. Dgcr8 loss blocked Pten null‐induced expansion of the basal‐like, but not luminal, cellular compartment. Furthermore, while late‐stage Pten knockout tumors exhibit decreased senescence‐associated beta‐galactosidase activity and increased proliferation, the simultaneous deletion of Dgcr8 blocked these changes resulting in levels similar to wild type. Sequencing of small RNAs in isolated epithelial cells uncovered numerous miRNA changes associated with PTEN loss. Consistent with a Pten–Dgcr8 association, analysis of a large cohort of human prostate tumors shows a strong correlation between Akt activation and increased Dgcr8 mRNA levels. Together, these findings uncover a critical role for microRNAs in enhancing proliferation and enabling the expansion of the basal cell compartment associated with tumor progression following Pten loss.