Down-regulation of PDCD4 expression is an independent predictor of poor prognosis in human renal cell carcinoma patients

Li, Xiancheng; Xin, Shiyong; Yang, Deyong; Li, Xiunan; He, Zhijun; Che, Xiangyu; Wang, Jianbo; Chen, Feng; Wang, Xuejian; Song, Xishuang

doi:10.1007/s00432-011-1121-y

Cited by 26 publications

(27 citation statements)

References 27 publications

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“…Moreover, Li et al observed that PDCD4 expression was found to be significantly associated with RCC metastasis, tumor, T-stage and tumor grade. Furthermore, decreased PDCD4 expression proved to be an independent prognostic marker for overall survival in addition to the presence of tumor metastasis and high tumor grade, and mean overall survival was significantly decreased in the low PDCD4 group compared to the high PDCD4 group [31]. All these findings demonstrate that PDCD4 is potentially not only a tumor suppressor gene, but also an invasion inhibitor in RCC.…”

Section: Discussionmentioning

confidence: 82%

MicroRNA-21 (miR-21) Post-Transcriptionally Downregulates Tumor Suppressor PDCD4 and Promotes Cell Transformation, Proliferation, and Metastasis in Renal Cell Carcinoma

Xin

et al. 2014

Cell Physiol Biochem

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Objectives: MiR-21 induces neoplastic transformation, cell proliferation, and metastasis and downregulates programmed cell death4 (PDCD4) in some cancers. The aim of this study was to investigate the roles and interactions of PDCD4 and miR-21 in human renal cell carcinoma (RCC). Materials and Methods: A total of 32 paired tumor and normal tissue specimens from RCC patients as well as three renal cancer cell lines (786-O, A498, caki-1) and one normal epithelial kidney cell line (HK-2) were studied. The expression levels of PDCD4 (protein and mRNA) and miR-21 were examined by Western blot analysis and by qRT-PCR and luciferase reporter assays. Furthermore, we transfected 786-O cells with pre-miR-21 (mimics) and anti-miR-21 (inhibitor) and then again analyzed the expression of PDCD4 protein and mRNA, and determined cell proliferation and transformation capabilities by EDU and soft agar colony formation assay. Results: MiR-21 expression was significantly upregulated in RCC, metastatic RCC specimens and renal cancer cell lines (A498, 786-O, caki-1) compared to normal non-metastatic RCC specimens and HK-2 cells (P<0.05). In contrast, PDCD4 protein expression significantly decreased (P<0.05), whereas PDCD4 mRNA expression remained unaltered (P>0.05). Moreover, we observed a significant reduction in PDCD4 protein levels in miR-21mimic-transfected cells, but a significant increase in miR-21inhibitor-transfected cells (P<0.05), whereas PDCD4 mRNA was practically unaltered (P>0.05). Furthermore, miR-21mimic-transfected cells exhibited increased cell proliferation and transformation capacity according to EDU analysis and soft agar formation assay, whereas miR-21inhibitor-transfected cells exhibited the opposite phenomenon(P<0.05). Conclusions: MiR-21 not only promoted cancer cell hyperplasia and contributed to tumor cell transformation and metastasis, but also post-transcriptionally downregulated PDCD4 protein expression. PDCD4 and miR-21 expression levels potentially play an important role in renal cell cancer.

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Section: Discussionmentioning

confidence: 82%

MicroRNA-21 (miR-21) Post-Transcriptionally Downregulates Tumor Suppressor PDCD4 and Promotes Cell Transformation, Proliferation, and Metastasis in Renal Cell Carcinoma

Xin

et al. 2014

Cell Physiol Biochem

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“…1A shows reduced levels of PDCD4 in both these renal carcinoma cells as compared to normal renal proximal tubular epithelial cell HK2 (Supplementary Fig. S1A) [33]. To test the role of miR-21 in targeting PDCD4, we used a reporter plasmid containing 3′UTR of PDCD4 mRNA.…”

Section: Resultsmentioning

confidence: 99%

“…Also, its role in invasion of several solid tumors has been reported [21, 34, 38, 39, 49, 60–62]. More recently, decreased expression of PDCD4 has been reported in renal tumors [33]. Transcriptional and epigenetic regulations represent major mechanisms for PDCD4 expression [63–65].…”

Section: Discussionmentioning

confidence: 99%

“…Expression of PDCD4 is frequently inhibited in many cancers including lung, breast, hepatoma, glial, tongue and skin tumors [39]. Also inhibition of PDCD4 expression in renal tumors and in renal cancer-derived cell lines is reported albeit with discrepancy between transcript and protein levels suggesting a posttranscriptional regulation of PDCD4 expression [33, 42]. In many cancers, PDCD4 expression is regulated by different miRNAs.…”

Section: Introductionmentioning

confidence: 99%

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microRNA-21-induced dissociation of PDCD4 from rictor contributes to Akt-IKKβ-mTORC1 axis to regulate renal cancer cell invasion

Bera

Das

Ghosh‐Choudhury

et al. 2014

Experimental Cell Research

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Renal cancer metastasis may result from oncogenic forces that contribute to the primary tumor. We have recently identified microRNA-21 as an oncogenic driver of renal cancer cells. The mechanism by which miR-21 controls renal cancer cell invasion is poorly understood. We show that miR-21 directly downregulates the proapoptotic protein PDCD4 to increase migration and invasion of ACHN and 786-O renal cancer cells as a result of phosphorylation/activation of Akt and IKKβ, which activate NFκB-dependent transcription. Constitutively active (CA) Akt or CA IKKβ blocks PDCD4-mediated inhibition and restores renal cancer cell migration and invasion. PDCD4 inhibits mTORC1 activity, which was reversed by CA IKKβ. Moreover, CA mTORC1 restores cell migration and invasion inhibited by PDCD4- and dominant negative IKKβ. Moreover, PDCD4 negatively regulates mTORC2-dependent Akt phosphorylation upstream of this cascade. We show that PDCD4 forms a complex with rictor, an exclusive component of mTORC2, and that this complex formation is reduced in renal cancer cells due to increased miR-21 expression resulting in enhanced phosphorylation of Akt. Thus our results identify a previously unrecognized signaling node where high miR-21 levels reduce rictor-PDCD4 interaction to increase phosphorylation of Akt and contribute to metastatic fitness of renal cancer cells.

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“…Expression of PDCD4 is often suppressed in tumors and has been associated with poor survival outcomes [65][66][67][68]. A negative regulator of PDCD4 in tumorigenesis is miR-21, a micro-RNA that has also been widely implicated in tumor progression and is associated with poor prognosis in many cancers including, but not limited to lung cancers, breast cancers, gastric cancers, renal cell carcinomas, and glioblastomas [69][70][71][72][73][74][75][76]. Tumor suppressing properties of PDCD4 have also been observed within a laboratory setting, as PDCD4 −/− mice develop B cell lymphomas and epidermistargeted expression of PDCD4 suppresses carcinogen-induced tumor development [77,78], while administration of PDCD4 to an activated K-Ras lung tumor model via aerosol delivery inhibited carcinogenesis [79].…”

Section: Pdcd4 and Eif4amentioning

confidence: 99%

Targeting the eIF4A RNA helicase as an anti-neoplastic approach

Chu

Pelletier

2015

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Down-regulation of PDCD4 expression is an independent predictor of poor prognosis in human renal cell carcinoma patients

Abstract: PDCD4 expression strongly correlated to RCC stage, tumor grade, tumor metastasis and tumor-related death. PDCD4 expression was also appears to be a marker in RCC prognosis.

Cited by 26 publications

References 27 publications

MicroRNA-21 (miR-21) Post-Transcriptionally Downregulates Tumor Suppressor PDCD4 and Promotes Cell Transformation, Proliferation, and Metastasis in Renal Cell Carcinoma

MicroRNA-21 (miR-21) Post-Transcriptionally Downregulates Tumor Suppressor PDCD4 and Promotes Cell Transformation, Proliferation, and Metastasis in Renal Cell Carcinoma

microRNA-21-induced dissociation of PDCD4 from rictor contributes to Akt-IKKβ-mTORC1 axis to regulate renal cancer cell invasion

Targeting the eIF4A RNA helicase as an anti-neoplastic approach

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