Abstract
BackgroundThe tumor suppressor Programmed Cell Death 4 (PDCD4) has been found to be under-expressed in several cancers and associated with disease progression and metastasis. There are no current studies characterizing PDCD4 expression and its clinical relevance in Oral Squamous Cell Carcinoma (OSCC). Since nodal metastasis is a major prognostic factor in OSCC, we focused on determining whether PDCD4 under-expression was associated with patient nodal status and had functional relevance in OSCC invasion. We also examined PDCD4 regulation by microRNA 21 (miR-21) in OSCC.ResultsPDCD4 mRNA expression levels were assessed in 50 OSCCs and 25 normal oral tissues. PDCD4 was under-expressed in 43/50 (86%) OSCCs, with significantly reduced mRNA levels in patients with nodal metastasis (p = 0.0027), and marginally associated with T3-T4 tumor stage (p = 0.054). PDCD4 protein expression was assessed, by immunohistochemistry (IHC), in 28/50 OSCCs and adjacent normal tissues; PDCD4 protein was absent/under-expressed in 25/28 (89%) OSCCs, and marginally associated with nodal metastasis (p = 0.059). A matrigel invasion assay showed that PDCD4 expression suppressed invasion, and siRNA-mediated PDCD4 loss was associated with increased invasive potential of oral carcinoma cells. Furthermore, we showed that miR-21 levels were increased in PDCD4-negative tumors, and that PDCD4 expression may be down-regulated in OSCC by direct binding of miR-21 to the 3'UTR PDCD4 mRNA.ConclusionsOur data show an association between the loss of PDCD4 expression, tumorigenesis and invasion in OSCC, and also identify a mechanism of PDCD4 down-regulation by microRNA-21 in oral carcinoma. PDCD4 association with nodal metastasis and invasion suggests that PDCD4 may be a clinically relevant biomarker with prognostic value in OSCC.
Highlights
Oral squamous cell carcinomas (OSCCs) are malignant oral cavity tumors that account for 24% of all head and neck cancers [1]
Lower Programmed Cell Death 4 (PDCD4) mRNA levels were detected in OSCCs from patients with more advanced tumor stage, and were lower in tumors from patients with nodal metastasis (Figure 1)
PDCD4 mRNA levels, survival and disease-free survival (DFS) Univariate analysis of survival and DFS showed that patients with lower PDCD4 mRNA levels showed worse survival (HR = 0.014, 95% Confidence Intervals (CI): 0.001-0.39, p = 0.0118) and poorer DFS (HR = 0.134, 95% CI: 0.019-0.961, p = 0.0456) (Figure 2)
Summary
Oral squamous cell carcinomas (OSCCs) are malignant oral cavity tumors that account for 24% of all head and neck cancers [1]. PDCD4 levels were decreased in primary patient tumor samples from lung cancer [8], hepatocellular carcinoma [10], breast carcinoma [11], colon cancer [12,13], glioma [14], pancreatic cancer [15] and esophageal carcinoma [16]. In epithelial tumors, such as breast cancer, PDCD4 protein expression levels were slightly reduced in ductal carcinoma in situ, but markedly decreased in invasive ductal carcinoma, suggesting that its loss may be required for invasion [17]. The tumor suppressor Programmed Cell Death 4 (PDCD4) has been found to be under-expressed in several cancers and associated with disease progression and metastasis. We examined PDCD4 regulation by microRNA 21 (miR-21) in OSCC
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