Tumor suppressor Pdcd4 inhibits invasion/intravasation and regulates urokinase receptor (u-PAR) gene expression via Sp-transcription factors

Leupold, Jörg Hendrik; Yang, Huiling; Colburn, Nancy H.; Asangani, Irfan A.; Post, Stefan; Allgayer, Heike

doi:10.1038/sj.onc.1210234

Cited by 153 publications

(146 citation statements)

References 54 publications

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“…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. Similarly, the expression of mir-21 and suppression of PDCD4 has been previously reported in BC and colorectal cancer (Leupold et al, 2007;Lu et al, 2008). Other studies had also shown that PDCD4 is the direct targets of mir-21 (Meng et al, 2007;Zhu et al, 2007;Frankel et al, 2008).…”

Section: Discussionmentioning

confidence: 92%

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

Hafez

Hassan²,

Zekri³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Section: Discussionmentioning

confidence: 92%

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

Hafez

Hassan²,

Zekri³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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“…In addition to being translationally repressed by miR-21 (Asangani et al, 2008;Frankel et al, 2008;Zhu et al, 2008), PDCD4 itself is a translational repressor, inhibiting the translation initiation factor eIF4A (Yang et al, 2003a). PDCD4 inhibits the activity of AP-1 and other transcription factors, including b-catenin/Tcf (Wang et al, 2007) and Sp1/Sp3 (Leupold et al, 2007). PDCD4 affects AP-1 by indirect mechanisms, likely mediated by the decreased synthesis of MAP4K1, affecting the activity of the JNKK-JNKc-Jun pathway (Bitomsky et al, 2004;Yang et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation

et al. 2008

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The transcription factor AP-1 plays key roles in tumorigenesis, by regulating a variety of protein-coding genes, implicated in multiple hallmarks of cancer. Among non-coding genes, no AP-1 target has been described yet in tumorigenesis. MicroRNAs (miRNAs) are negative post-transcriptional regulators of protein-coding genes. miRNA expression signatures are highly relevant in cancer and several tumor-associated miRNAs (oncomirs) play critical roles in oncogenesis. Here, we show that the miRNA miR-21, which represents the most frequently upregulated oncomir in solid tumors, is induced by AP-1 in response to RAS. By analyzing validated miR-21 targets, we have found that the tumor suppressors PTEN and PDCD4 are downregulated by RAS in an AP-1-and miR-21-dependent fashion. We further show that, given the role of PDCD4 as negative regulator of AP-1, the miR-21-mediated downregulation of PDCD4 is essential for the maximal induction of AP-1 activity in response to RAS. Our data reveal a novel mechanism of positive autoregulation of the AP-1 complex in RAS transformation and disclose the function of oncomirs as critical targets and regulators of AP-1 in tumorigenesis.

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“…Leupold et al [21] demonstrated that PDCD4 inhibited the invasion of colon cancer cells by a mechanism that involved decreased transcription of uPAR. We determined the mRNA levels of uPAR in MCF-7 and MCF-7/PDCD4 cells.…”

Section: Pdcd4 Increases Timp-2 Expression To Inhibit Breast Cancer Imentioning

confidence: 99%

“…This study implicates that PDCD4 may have an important role in regulating the invasive activity of breast tumors. Increased expression of PDCD4 has been shown to decrease invasion of colon cancer cells [21,22], whereas downregulation of PDCD4 has been shown to promote invasion of colon cancer cells [23]. However, whether PDCD4 has a role in breast cancer cell invasion has not been reported.…”

Section: Introductionmentioning

confidence: 99%

Programmed Cell Death 4 inhibits breast cancer cell invasion by increasing Tissue Inhibitor of Metalloproteinases-2 expression

Nieves-Alicea

Colburn

Simeone

et al. 2008

Breast Cancer Res Treat

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High levels of the cyclooxygenase-2 (COX-2) protein have been associated with invasion and metastasis of breast tumors. Both prostaglandin E 2 (PGE 2 ) and interleukin-8 (IL-8) have been shown to mediate the invasive activity of COX-2 in breast cancer cells. Here we expand these studies to determine how COX-2 uses PGE 2 and IL-8 to induce breast cancer cell invasion. We demonstrated that PGE 2 and IL-8 decreased the expression of the tumor suppressor protein Programmed Cell Death 4 (PDCD4). We hypothesized that suppression of PDCD4 expression is vital to the invasive activity of PGE 2 and IL-8. In MCF-7 cells overexpressing PDCD4 (MCF-7/PDCD4), PGE 2 and IL-8 failed to induce invasion, in contrast to the parental MCF-7 cells, thus indicating that PDCD4 blocks breast cancer cell invasion. MCF-7/PDCD4 cells produced higher levels of the Tissue Inhibitor of Metalloproteinases-2 (TIMP-2) than the parental cells. Silencing TIMP-2 mRNA in MCF-7/PDCD4 cells reversed the anti-invasive effects of PDCD4, allowing PGE 2 and IL-8 to induce the invasion of these cells. Here we report the novel findings that suppression of PDCD4 expression is vital for the invasive activity of COX-2 mediated by PGE 2 and IL-8, and that PDCD4 increases TIMP-2 expression to inhibit breast cancer cell invasion.

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Tumor suppressor Pdcd4 inhibits invasion/intravasation and regulates urokinase receptor (u-PAR) gene expression via Sp-transcription factors

Cited by 153 publications

References 54 publications

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

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

An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation

Programmed Cell Death 4 inhibits breast cancer cell invasion by increasing Tissue Inhibitor of Metalloproteinases-2 expression

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