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卵巢癌中肿瘤抑制功能和程序性细胞死亡因子 4（PDCD4）的调节。

Tumour suppressive function and modulation of programmed cell death 4 (PDCD4) in ovarian cancer.

机构信息

Department of Obstetrics & Gynaecology, Queen Mary Hospital, the University of Hong Kong, Hong Kong, Hong Kong.

出版信息

PLoS One. 2012;7(1):e30311. doi: 10.1371/journal.pone.0030311. Epub 2012 Jan 17.

DOI:10.1371/journal.pone.0030311
PMID:22272332
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3260274/
Abstract

BACKGROUND

Programmed cell death 4 (PDCD4), originally identified as the neoplastic transformation inhibitor, was attenuated in various cancer types. Our previous study demonstrated a continuous down-regulation of PDCD4 expression in the sequence of normal-borderline-malignant ovarian tissue samples and a significant correlation of PDCD4 expression with disease-free survival. The objective of the current study was to further investigate the function and modulation of PDCD4 in ovarian cancer cells.

PRINCIPAL FINDINGS

We demonstrated that ectopic PDCD4 expression significantly inhibited cell proliferation by inducing cell cycle arrest at G(1) stage and up-regulation of cell cycle inhibitors of p27 and p21. Cell migration and invasion were also inhibited by PDCD4. PDCD4 over-expressing cells exhibited elevated phosphatase and tensin homolog (PTEN) and inhibited protein kinase B (p-Akt). In addition, the expression of PDCD4 was up-regulated and it was exported to the cytoplasm upon serum withdrawal treatment, but it was rapidly depleted via proteasomal degradation upon serum re-administration. Treatment of a phosphoinositide 3-kinase (PI3K) inhibitor prevented the degradation of PDCD4, indicating the involvement of PI3K-Akt pathway in the modulation of PDCD4.

CONCLUSION

PDCD4 may play a critical function in arresting cell cycle progression at key checkpoint, thus inhibiting cell proliferation, as well as suppressing tumour metastasis. The PI3K-Akt pathway was implied to be involved in the regulation of PDCD4 degradation in ovarian cancer cells. In response to the stress condition, endogenous PDCD4 was able to shuttle between cell compartments to perform its diverted functions.

摘要

背景

程序性细胞死亡因子 4（PDCD4）最初被鉴定为肿瘤转化抑制剂，在各种癌症类型中均有减弱。我们之前的研究表明，在正常-交界性-恶性卵巢组织样本的序列中，PDCD4 表达持续下调，并且 PDCD4 表达与无病生存率显著相关。本研究的目的是进一步研究 PDCD4 在卵巢癌细胞中的功能和调节作用。

主要发现

我们证明，异位 PDCD4 表达通过诱导 G1 期细胞周期停滞和上调细胞周期抑制剂 p27 和 p21，显著抑制细胞增殖。PDCD4 还抑制细胞迁移和侵袭。PDCD4 过表达细胞表现出更高的磷酸酶和张力蛋白同系物（PTEN）和抑制蛋白激酶 B（p-Akt）。此外，PDCD4 的表达在血清撤出处理时上调并被输出到细胞质，但在血清再给予时迅速通过蛋白酶体降解而耗尽。磷酸肌醇 3-激酶（PI3K）抑制剂的处理阻止了 PDCD4 的降解，表明 PI3K-Akt 途径参与了 PDCD4 的调节。

结论

PDCD4 可能在关键检查点阻止细胞周期进程中发挥关键功能，从而抑制细胞增殖和肿瘤转移。PI3K-Akt 途径被暗示参与了卵巢癌细胞中 PDCD4 降解的调节。在内源性应激条件下，PDCD4 能够在细胞区室之间穿梭，以执行其不同的功能。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b048/3260274/9d9d01fc58d9/pone.0030311.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b048/3260274/bc826281ec0d/pone.0030311.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b048/3260274/7d53150aba32/pone.0030311.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b048/3260274/77e5ffbfe7da/pone.0030311.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b048/3260274/8ab4e0026c81/pone.0030311.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b048/3260274/9d9d01fc58d9/pone.0030311.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b048/3260274/bc826281ec0d/pone.0030311.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b048/3260274/7d53150aba32/pone.0030311.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b048/3260274/77e5ffbfe7da/pone.0030311.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b048/3260274/8ab4e0026c81/pone.0030311.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b048/3260274/9d9d01fc58d9/pone.0030311.g005.jpg

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