27250

PDCD4

programmed cell death 4 (neoplastic transformation inhibitor);PDCD4;programmed cell death 4 (neoplastic transformation inhibitor)

neoplastic transformation inhibitor protein|nuclear antigen H731|programmed cell death protein 4|protein 197/15a

10q24

protein-coding

The novel tumor suppressor Pdcd4 inhibits neoplastic transformation, tumor progression and translation. Furthermore, we and others have recently shown that Pdcd4 suppresses invasion and intravasation, at least in part by suppressing expression of the invasion-related urokinase receptor (u-PAR) gene via the transcription factors Sp1/Sp3. Nevertheless, relatively little is known about mechanisms that regulate Pdcd4 expression in cancer. MicroRNAs (miRNAs) have been recently discovered and shown to be naturally occurring non-coding RNAs that control gene expression via specific sites within the 3UTR of target miRNAs. This short review will focus on our recent finding that the microRNA miR-21 posttranscriptionally regulates Pdcd4, as well as invasion, intravasation, and metastasis. Furthermore, we will review the first translational and clinical results concerning the prognostic value of Pdcd4, in particular our own data that show Pdcd4 to be a novel and independent prognostic factor in colorectal cancer, and a potential supportive diagnostic tool for discriminating normal colonic tissues from benign adenomas and colorectal carcinomas.

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.