Progesterone Receptor B signaling Reduces Breast Cancer Cell Aggressiveness: Role of Cyclin-D1/Cdk4 Mediating Paxillin Phosphorylation

Montalto, Francesca; Giordano, Francesca; Chiodo, Chiara; Marsico, Stefania; Mauro, Loredana; Sisci, Diego; Aquila, Saveria; Lanzino, Marilena; Panno, Maria Luisa; Andò, Sebastiano; Amicis, Francesca De

doi:10.3390/cancers11081201

Cited by 17 publications

(19 citation statements)

References 61 publications

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“…We also observed a decrease in phospho-paxillin and Rac1 in miR-141 overexpressing cells compared to controls. Elevated paxillin phosphorylation is common in cancer tissues and is associated with tumorigenesis, EMT, and metastasis 15,16,50 . Paxillin interacts with numerous molecules, controlling the Rho family of GTPases, that are crucial regulators of adhesion dynamics 16,51 .…”

Section: Discussionmentioning

confidence: 99%

“…Elevated paxillin phosphorylation is common in cancer tissues and is associated with tumorigenesis, EMT, and metastasis 15,16,50 . Paxillin interacts with numerous molecules, controlling the Rho family of GTPases, that are crucial regulators of adhesion dynamics 16,51 . Rac1 GTPase is required for cell migration and its hyperactivation results in cancer invasiveness and progression 52 .…”

Section: Discussionmentioning

confidence: 99%

“…[10][11][12][13] are common EMT phenomena. Often the progression of cancer through EMT is significantly induced by the interaction of Cyclin-D with its binding partner, Cdk4 which act as transcriptional regulators controlling cell proliferation and migration [14][15][16] . It is well known that Cyclin-D regulates the rate-limiting step in cell cycle progression from G1 to S phase.…”

Section: Introductionmentioning

confidence: 99%

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LncRNA CDKN2B-AS1/miR-141/cyclin D network regulates tumor progression and metastasis of renal cell carcinoma

et al. 2020

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The molecular heterogeneity of renal cell carcinoma (RCC) complicates the therapeutic interventions for advanced metastatic disease and thus its management remains a significant challenge. This study investigates the role of the lncRNA CDKN2B-AS1 and miR-141-3p interactions in the progression and metastasis of kidney cancer. Human renal cancer cell lines (ACHN and Caki1), normal RPTEC cells, tissue cohorts, and a series of in vitro assays and in vivo mouse model were used for this study. An overexpression of CDKN2B-AS1 was observed in RCC compared to normal samples in TCGA and our in-house SFVAMC tissue cohorts. Reciprocally, we observed reduced expression of miR-141 in RCC compared to normal in the same cohorts. CDKN2B-AS1 shares regulatory miR-141 binding sites with CCND1 and CCND2 genes. Direct interactions of CDKN2B-AS1/miR-141/Cyclin D1-D2 were confirmed by RNA immunoprecipitation and luciferase reporter assays indicating that CDKN2B-AS1/miR-141/Cyclin D1-D2 acts as a ceRNA network in RCC. Functionally, attenuation of CDKN2B-AS1 and/or overexpression of miR-141 inhibited proliferation, clonogenicity, migration/invasion, induced apoptosis in vitro and suppressed tumor growth in xenograft mouse model. Further, overexpression of CDKN2B-AS1 is positively correlated with poor overall survival of RCC patients. Expression of miR-141 also robustly discriminated malignant from non-malignant tissues and its inhibition in normal RPTEC cells induced procancerous characteristics. CDKN2B-AS1 attenuation or miR-141 overexpression decreased CCND1/CCND2 expression, resulting in reduced RAC1/pPXN that are involved in migration, invasion and epithelial-mesenchymal transition. This study, for the first time, deciphered the role of CDKN2B-AS1/miR-141/Cyclin D axis in RCC and highlights this network as a promising therapeutic target for the regulation of EMT driven metastasis in RCC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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LncRNA CDKN2B-AS1/miR-141/cyclin D network regulates tumor progression and metastasis of renal cell carcinoma

et al. 2020

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“…Notably, Pxn contains many phosphorylation sites, and it was demonstrated that Pxn acts as a substrate for the Cyclin D1/CDK4 complex [ 86 ]. We recently reported that low levels of Pxn phosphorylation at Ser 83, resulting to the reduced Cyclin D1/CDK4 functional interaction, led to the inhibition of mediators of membrane ruffles and actin rearrangements such as Rac1 and its effector Pak, as evidenced by the reduction of pSer144-Pak1 levels [ 88 ] (see Figure 2 ).…”

Section: Membrane Associated and Cytoplasmatic Cyclin D1: Linking mentioning

confidence: 99%

Cyclin D1 in Cancer: A Molecular Connection for Cell Cycle Control, Adhesion and Invasion in Tumor and Stroma

Montalto

Amicis

2020

Cells

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267

152

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Cyclin D1, an important regulator of cell cycle, carries out a central role in the pathogenesis of cancer determining uncontrolled cellular proliferation. In normal cells, Cyclin D1 expression levels are strictly regulated, conversely, in cancer, its activity is intensified in various manners. Different studies demonstrate that CCDN1 gene is amplified in several tumor types considering it as a negative prognostic marker of this pathology. Cyclin D1 is known for its role in the nucleus, but recent clinical studies associate the amount located in the cytoplasmic membrane with tumor invasion and metastasis. Cyclin D1 has also other functions: it governs the expression of specific miRNAs and it plays a crucial role in the tumor-stroma interactions potentiating most of the cancer hallmarks. In the present review, we will summarize the current scientific evidences that highlight the involvement of Cyclin D1 in the pathogenesis of different types of cancer, best of all in breast cancer. We will also focus on recent insights regarding the Cyclin D1 as molecular bridge between cell cycle control, adhesion, invasion, and tumor/stroma/immune-system interplay in cancer.

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“…Recent findings in cancer progression investigate new possible molecular mechanisms regulating invasion, epithelial mesenchymal transition (EMT) [76,77], and the possible link with autophagy. It is reported that (synaptojanin 2 binding protein) SYNJ2BP, crucially involved in the pathogenesis of metastatic breast tumors, is responsible of the degradation of PTEN through the lysosomes; particularly, SYNJ2BP stimulates the recruitment of PTEN at autophagy-lysosomes, the autophagosome cargo (p62) expression, and LC3-I to LC3-II conversion.…”

Section: Regulation Of Emt and Invasion Through Autophagy By Ptenmentioning

confidence: 99%

The Tumor Suppressor PTEN as Molecular Switch Node Regulating Cell Metabolism and Autophagy: Implications in Immune System and Tumor Microenvironment

Aquila

Santoro

Caputo

et al. 2020

Cells

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Recent studies conducted over the past 10 years evidence the intriguing role of the tumor suppressor gene Phosphatase and Tensin Homolog deleted on Chromosome 10 PTEN in the regulation of cellular energy expenditure, together with its capability to modulate proliferation and survival, thus expanding our knowledge of its physiological functions. Transgenic PTEN mice models are resistant to oncogenic transformation, present decreased adiposity and reduced cellular glucose and glutamine uptake, together with increased mitochondrial oxidative phosphorylation. These acquisitions led to a novel understanding regarding the role of PTEN to counteract cancer cell metabolic reprogramming. Particularly, PTEN drives an “anti-Warburg state” in which less glucose is taken up, but it is more efficiently directed to the mitochondrial Krebs cycle. The maintenance of cellular homeostasis together with reduction of metabolic stress are controlled by specific pathways among which autophagy, a catabolic process strictly governed by mTOR and PTEN. Besides, a role of PTEN in metabolic reprogramming and tumor/stroma interactions in cancer models, has recently been established. The genetic inactivation of PTEN in stromal fibroblasts of mouse mammary glands, accelerates breast cancer initiation and progression. This review will discuss our novel understanding in the molecular connection between cell metabolism and autophagy by PTEN, highlighting novel implications regarding tumor/stroma/immune system interplay. The newly discovered action of PTEN opens innovative avenues for investigations relevant to counteract cancer development and progression.

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Progesterone Receptor B signaling Reduces Breast Cancer Cell Aggressiveness: Role of Cyclin-D1/Cdk4 Mediating Paxillin Phosphorylation

Cited by 17 publications

References 61 publications

LncRNA CDKN2B-AS1/miR-141/cyclin D network regulates tumor progression and metastasis of renal cell carcinoma

LncRNA CDKN2B-AS1/miR-141/cyclin D network regulates tumor progression and metastasis of renal cell carcinoma

Cyclin D1 in Cancer: A Molecular Connection for Cell Cycle Control, Adhesion and Invasion in Tumor and Stroma

The Tumor Suppressor PTEN as Molecular Switch Node Regulating Cell Metabolism and Autophagy: Implications in Immune System and Tumor Microenvironment

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