An essential role of PDCD4 in progression and malignant proliferation of gastrointestinal stromal tumors
Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan 250012, Shandong, China.Medical Oncology (Impact Factor: 2.63). 08/2011; 29(3):1758-64. DOI: 10.1007/s12032-011-0042-6
Programmed cell death 4 (PDCD4) is a tumor suppressor that can inhibit tumorigenesis by suppressing activator protein (AP)-1 activation and protein translation. Lost or decreased PDCD4 expression has been found in multiple types of human cancers, which was also associated with progression and metastasis of the tumors. However, the status and significance of PDCD4 in gastrointestinal stromal tumors have not been evaluated. In the present study, we examined the PDCD4 expression in a total of 63 gastrointestinal stromal tumor samples at both mRNA and protein levels by RT-PCR, western blot, and immunohistochemistry. We demonstrated that the expression of PDCD4 mRNA was diminished in 68% (17/25) of the tumor samples, and the level of PDCD4 protein appeared to be decreased in 66.7% (42/63) of the samples, as compared to adjacent normal gastrointestinal tissues, which expressed high levels of PDCD4 mRNA and protein. In addition, altered expression of PDCD4 was associated with clinicopathological parameters including risk group, tumor size, and mitosis. Moreover, PDCD4 expression had a negative correlation with the Ki-67 labeling index (r = -0.6059, P < 0.0001). All these results suggest that downregulation of PDCD4 expression may have an essential role in the progression and malignant proliferation of human gastrointestinal stromal tumors.
- [Show abstract] [Hide abstract]
ABSTRACT: Programmed cell death 4 (PDCD4) is a novel tumor suppressor gene that can inhibit tumor neoplastic transformation and progression in cultured cells and gene knock-out mouse models. Lost or decreased PDCD4 expression has been associated with progression and prognosis of multiple types of human tumors. However, the expression and clinical significance of PDCD4 in nasal inverted papillomas (NIPs) has not been investigated. We compared PDCD4 expression in 64 samples of NIPs, 23 of associated squamous cell carcinomas (SCCs), and 19 normal nasal samples at mRNA and protein levels by RT-PCR, western blot analysis, and immunohistochemistry. PDCD4 mRNA expression was reduced in 52% of NIP frozen samples (13/25), and the protein level was diminished in 56.3% of samples (36/64) as compared with 19 normal nasal samples, which expressed high levels of PDCD4 mRNA and protein. Furthermore, altered expression of PDCD4 was associated with the clinicopathological features Krouse stage and dysplasia. Importantly, we found a strong negative correlation of PDCD4 expression and Ki-67 labeling index in NIPs (r = -0.6645, p < 0.001). In addition, the 3 tissue-sample groups significantly differed in PDCD4 expression and Ki-67 labeling index. Thus, PDCD4 expression may play a key role in pre-cancerous lesions of human NIPs and may help predict malignant progression from benign nasal tumors to associated SCC.
- [Show abstract] [Hide abstract]
ABSTRACT: Glioblastoma multiforme (GBM) is the most aggressive and the commonest primary brain tumor with a tendency for local invasiveness. The pathways of neoplasia, invasion and inflammation are inextricably linked in cancer and aberrations in several regulatory pathways for these processes have been identified. Here we have studied the FAT1 (Homo sapiens FAT tumor-suppressor homolog 1 (Drosophila)) gene to identify its role in the tumorigenecity of the gliomas. The expression of FAT1 was found to be high in grade IV glioma cell lines (U87MG, A172, U373MG and T98G) but low in grade III glioma cell lines (GOS3 and SW1088). Two cell lines (U87MG and A172) with high FAT1 expression were chosen for in vitro FAT1-knockdown studies. FAT1 knockdown by small interfering RNA resulted in decreased migration and invasion of both the cell lines along with increased expression of the tumor-suppressor gene programmed cell death 4 (PDCD4). Increased PDCD4 expression led to the attenuation of activator protein-1 (AP-1) transcription by inhibiting c-Jun phosphorylation and resulted in concomitant decrease in the expression of AP-1-target genes like MMP3, VEGF-C and PLAU, the pro-inflammatory regulator COX-2 and cytokines IL1 beta and IL-6. Conversely, simultaneous silencing of PDCD4 and FAT1 in these cells significantly enhanced AP-1 activity and expression of its target genes, resulting in increase in mediators of inflammation and in enhanced migratory and invasive properties of the cells. We also observed a negative correlation between the expression of FAT1 and PDCD4 (P = 0.0145), a positive correlation between the expression of FAT1 and COX-2 (P = 0.048) and a similar positive trend between FAT1 and IL-6 expression in 35 primary human GBM samples studied. Taken together, this study identifies a novel signaling mechanism mediated by FAT1 in regulating the activity of PDCD4 and thereby the key transcription factor AP-1, which then affects known mediators of neoplasia and inflammation.
- [Show abstract] [Hide abstract]
ABSTRACT: Programmed cell death 4 (PDCD4) has been recognized as a tumor suppressor gene that may inhibit neoplastic transformation and tumor promotion/progression. It was demonstrated that PDCD4 expression was associated with prognosis of multiple types of tumors and cancers. However, PDCD4 expression in salivary adenoid cystic carcinoma (ACC) has not been studied. We analyzed PDCD4 protein level by immunohistochemistry in 96 cases of ACC and found that PDCD4 expression was downregulated in 64.6 % (62/96) of tumor samples compared with adjacent nontumor salivary gland tissues. Moreover, decreased PDCD4 expression was significantly associated with clinical stage of the disease (P < 0.01). Analyses of overall survival and disease-specific survival by Kaplan–Meier method revealed that poor prognosis of ACC patients was associated with decreased PDCD4 expression (χ 2 = 5.971, P = 0.013; χ 2 = 4.274, P = 0.029). Furthermore, multivariate Cox model analysis demonstrated that PDCD4 expression was an independent risk factor for ACC (P < 0.05). Thus, our study suggested, for the first time, that PDCD4 expression might have an essential role in the progression of ACC.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.