Programmed cell death 4 loss increases tumor cell invasion and is regulated by miR-21 in oral squamous cell carcinoma

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.

MicroRNAs and Metastasis-related Gene Expression in Egyptian Breast Cancer Patients

“…In a similar previous study on the expression of miRNAs, mir-21 was significantly up-regulated in BC (Iorio et al, 2005). Our data are consistent with other reports indicating that mir-21 expression increased with advanced clinical stage Reis et al, 2010) .…”

“…Down-regulation of PDCD4 at both the mRNA and protein levels significantly associated with regional disease, more advanced tumor stages, and poorer survival . (Reis et al, 2010). In the present study there was downregulation of PDCD4 in the breast cancer tissues compared to the adjacent non-neoplastic tissues and was associated with the increase in the expression of mir-21.…”

Interferon Stimulated Gene - ISG15 is a Potential Diagnostic Biomarker in Oral Squamous Cell Carcinomas

“…Studies have revealed differential expression of several genes in OSCC lesions such as cyclin D1, EGFR, Tetranectin, NuclearS100A7, Smad2, Smad6, DeltaNp63 and PCD4, that have been proposed as potential biomarker to predict transforming potential of precancerous lesions and prognosis of well differentiated carcinomas (Ginos et al, 2004;O'Donnell et al, 2005;Saintigny et al, 2009;Arellano-Garcia et al, 2010;Mangone et al, 2010;Reis et al, 2010;Tripathi et al, 2010). However, none of the molecules have had an expression level similar to the findings of present study.…”

Impact of microRNA dynamics on cancer hallmarks: An oral cancer scenario

“…33 A large number of other significant oncogenic and tumor suppressor targets have been identified for miR-21 in head and neck and other cancers including Ras, programmed cell death 4 (PDCD4), reversion inducing cysteine rich protein with kazal motifs (RECK), and HNRPK. 49,65,[94][95][96] Moreover, Zhang et al 97 suggested that miR-21 could affect formation of reactive oxygen species (ROS) by directly attenuating superoxide dismutase (SOD) family member 3, SOD3, and by an indirect mechanism that limited tumor necrosis factor (TNF)-α production, thereby reducing SOD2 levels to promote tumorigenesis. Likewise, upregulation of miR-24 63 and miR-184 62 is associated with enhanced proliferation and reduced apoptosis.…”