Identification of a <i>Cyclin D1</i> Network in Prostate Cancer That Antagonizes Epithelial–Mesenchymal Restraint

Ju, Xiaoming; Casimiro, Mathew C.; Gormley, Michael; Meng, Hui; Jiao, Xuanmao; Katiyar, Sanjay; Crosariol, Marco; Chen, Ke; Wang, Min; Quong, Andrew A.; Lisanti, Michael P.; Ertel, Adam; Pestell, Richard G.

doi:10.1158/0008-5472.can-13-1313

Cited by 42 publications

(38 citation statements)

References 47 publications

(81 reference statements)

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“…30,31 Recent studies have suggested a dual role of cyclin D1 in promoting or inhibiting cellular migration in breast cancer 32 and prostate cancer. 33 In our study, CCND1 was observed to be a direct target of miR-374a and reversed miR-374a-mediated suppression of cell growth, metastasis and DDP chemoresistance. This was accomplished by activation of PI3K/AKT pathway via c-MYC as well as downstream cell cycle and EMT signals.…”

Section: Disscussionsupporting

confidence: 52%

miR-374a-CCND1-pPI3K/AKT-c-JUN feedback loop modulated by PDCD4 suppresses cell growth, metastasis, and sensitizes nasopharyngeal carcinoma to cisplatin

et al. 2016

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miR-374a has been reported to function as an oncogene during tumor pathogenesis. In this study, miR-374a is observed to reduce nasopharyngeal carcinoma (NPC) cell proliferation, migration, invasion, metastasis and cisplatin (DDP) resistance in vitro and in vivo. Mechanistic analyses indicate that miR-374a directly targets CCND1 to inactivate pPI3K/pAKT/c-JUN forming a negative feedback loop, as well as suppressing downstream signals related to cell cycle progression and epithelial-mesenchymal transition (EMT). Interestingly, we also observed that miR-374a direct targeting of CCND1 is modulated by tumor suppressor PDCD4 via suppressing pPI3K/pAKT/c-JUN signaling. In clinical specimens, miR-374a was positively and negatively correlated with expression of PDCD4 and CCND1, respectively. Our studies are the first to demonstrate that the miR-374a-CCND1-pPI3K/AKT-c-JUN feedback loop induced by PDCD4 supresses NPC cell growth, metastasis and chemotherapy resistance.

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Section: Disscussionsupporting

confidence: 52%

miR-374a-CCND1-pPI3K/AKT-c-JUN feedback loop modulated by PDCD4 suppresses cell growth, metastasis, and sensitizes nasopharyngeal carcinoma to cisplatin

et al. 2016

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“…For example, silencing of cyclin D1 increases the migratory capacity of MDA-MB-231 breast cancer cells [42]. The cyclin D1 network in prostate cancer antagonizes EMT and enhances cancer stem cell populations [43]. Overexpression of ZEB2 in A431 cells results in G 1 cell cycle arrest through direct transcriptional repression of cyclin D1 and ectopic cyclin D1 uncouples cell cycle arrest from EMT [44], whereas ZEB2 appears to induce proliferation of hippocampal precursors in vivo [45].…”

Section: Discussionmentioning

confidence: 99%

TMPRSS4 induces invasion and proliferation of prostate cancer cells through induction of Slug and cyclin D1

Lee

Min

et al. 2016

Oncotarget

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TMPRSS4 is a novel type II transmembrane serine protease found at the cell surface that is highly expressed in pancreatic, colon, and other cancer tissues. Previously, we demonstrated that TMPRSS4 mediates tumor cell invasion, migration, and metastasis. We also found that TMPRSS4 activates the transcription factor activating protein-1 (AP-1) to induce cancer cell invasion. Here, we explored TMPRSS4-mediated cellular functions and the underlying mechanisms. TMPRSS4 induced Slug, an epithelial-mesenchymal transition (EMT)-inducing transcription factor, and cyclin D1 through activation of AP-1, composed of c-Jun and activating transcription factor (ATF)-2, which resulted in enhanced invasion and proliferation of PC3 prostate cancer cells. In PC3 cells, not only c-Jun but also Slug was required for TMPRSS4-mediated proliferation and invasion. Interestingly, Slug induced phosphorylation of c-Jun and ATF-2 to activate AP-1 through upregulation of Axl, establishing a positive feedback loop between Slug and AP-1, and thus induced cyclin D1, leading to enhanced proliferation. Using data from The Cancer Genome Atlas, we found that Slug expression positively correlated with that of c-Jun and cyclin D1 in human prostate cancers. Expression of Slug was positively correlated with that of cyclin D1 in various cancer cell lines, whereas expression of other EMT-inducing transcription factors was not. This study demonstrates that TMPRSS4 modulates both invasion and proliferation via Slug and cyclin D1, which is a previously unrecognized pathway that may regulate metastasis and cancer progression.

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“…It has been reported that TGF-β induces EMT by Smad-mediated transcription regulation (11,14,15,38,39) and, moreover, TGF-β/BMP-SMAD4 signaling pathway promotes prostate cancer EMT and progression by PTEN deletion (40). Furthermore, in mammary epithelial cells, TGF-β can activate PI3K during EMT (41).…”

Section: Discussionmentioning

confidence: 99%

Transforming growth factor-β1-induced epithelial-mesenchymal transition in human esophageal squamous cell carcinoma via the PTEN/PI3K signaling pathway

Zhang

Wang

et al. 2014

Oncology Reports

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Epithelial-mesenchymal transition (EMT) is a crucial step for the invasive and metastatic properties of malignant tumor cells during tumor progression. Numerous signaling pathways are involved in the process of EMT in cancer, such as the EMT-inducing signal transforming growth factor (TGF)-β and the recently demonstrated PTEN/PI3K signaling pathway. To date, no data have been reported concerning the influence of PTEN/PI3K signaling pathway on EMT in human esophageal squamous cell carcinoma (ESCC) and how TGF-β1 and PTEN/PI3K act through multiple interconnected signaling pathways to trigger events associated with EMT and tumor progression. Our data showed that the PTEN/PI3K pathway was active in human ESCC tissues in vivo, particularly in ESCC with decreased E-cadherin and increased vimentin protein expression, poor differentiation, deep invasion and lymph node metastasis, which are responsible for EMT and tumor progression. In addition, in the human ESCC cell line (EC-1) in vitro, TGF-β1 treatment markedly induced EMT, including morphological alterations, a decrease of E-cadherin and an increase of vimentin levels and enhanced mobility and invasiveness. Furthermore, the PTEN/PI3K pathway was also activated in the process of TGF-β1-induced EMT in EC-1 cells in vitro, whereas inhibition of the PTEN/PI3K pathway by using pcDNA3.1 PTEN partially blocked TGF-β1-induced EMT and reduced mobility and invasiveness. These studies suggest that TGF-β1 and the PTEN/PI3K signaling pathway contribute to EMT and the PTEN/PI3K signaling pathway is a key regulator of TGF-β1‑induced EMT in ESCC. Disruption of the PTEN/PI3K pathway involved in TGF-β1-induced EMT may provide possible routes for therapeutic intervention to ESCC.

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Identification of a Cyclin D1 Network in Prostate Cancer That Antagonizes Epithelial–Mesenchymal Restraint

Cited by 42 publications

References 47 publications

miR-374a-CCND1-pPI3K/AKT-c-JUN feedback loop modulated by PDCD4 suppresses cell growth, metastasis, and sensitizes nasopharyngeal carcinoma to cisplatin

miR-374a-CCND1-pPI3K/AKT-c-JUN feedback loop modulated by PDCD4 suppresses cell growth, metastasis, and sensitizes nasopharyngeal carcinoma to cisplatin

TMPRSS4 induces invasion and proliferation of prostate cancer cells through induction of Slug and cyclin D1

Transforming growth factor-β1-induced epithelial-mesenchymal transition in human esophageal squamous cell carcinoma via the PTEN/PI3K signaling pathway

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