MYC Drives <i>Pten/Trp53</i>-Deficient Proliferation and Metastasis due to IL6 Secretion and AKT Suppression via PHLPP2

Nowak, Dawid G.; Cho, Hyejin; Herzka, Tali; Watrud, Kaitlin; DeMarco, Daniel V.; Wang, Victoria M.-Y.; Şentürk, Şerif; Fellmann, Christof; Ding, David; Beinortas, Tumas; Kleinman, David; Chen, Muhan; Sordella, Raffaella; Wilkinson, John E.; Castillo-Martín, Mireia; Cordon‐Cardo, Carlos; Robinson, Brian D.; Trotman, Lloyd C.

doi:10.1158/2159-8290.cd-14-1113

Cited by 73 publications

(68 citation statements)

References 58 publications

(82 reference statements)

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“…These include factors that activate Ras-MAPK signaling via cell surface receptors to augment MYC activity, including connective tissue growth factor (39), hepatocyte growth factor (40), and insulinlike growth factor binding proteins 2, 3, and 7 (which signal to EGFR indirectly via sphingosine-1-phosphate) (41). Stromal PSCs also produce Il6, which can activate STAT3 in a paracrine manner to transcriptionally activate MYC (42)(43)(44) and induce associated metabolic and transcriptional changes. We propose that microenvironmental regulation of gene expression cooperates with cellautonomous pathways to fortify cancer cell viability by co-opting an otherwise normal, and usually transient, wound-healing response.…”

Section: Discussionmentioning

confidence: 99%

Stromal cues regulate the pancreatic cancer epigenome and metabolome

Sherman

Tseng

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

131

112

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A fibroinflammatory stromal reaction cooperates with oncogenic signaling to influence pancreatic ductal adenocarcinoma (PDAC) initiation, progression, and therapeutic outcome, yet the mechanistic underpinning of this crosstalk remains poorly understood. Here we show that stromal cues elicit an adaptive response in the cancer cell including the rapid mobilization of a transcriptional network implicated in accelerated growth, along with anabolic changes of an altered metabolome. The close overlap of stroma-induced changes in vitro with those previously shown to be regulated by oncogenic Kras in vivo suggests that oncogenic Kras signaling-a hallmark and key driver of PDAC-is contingent on stromal inputs. Mechanistically, stroma-activated cancer cells show widespread increases in histone acetylation at transcriptionally enhanced genes, implicating the PDAC epigenome as a presumptive point of convergence between these pathways and a potential therapeutic target. Notably, inhibition of the bromodomain and extraterminal (BET) family of epigenetic readers, and of Bromodomain-containing protein 2 (BRD2) in particular, blocks stroma-inducible transcriptional regulation in vitro and tumor progression in vivo. Our work suggests the existence of a molecular "AND-gate" such that tumor activation is the consequence of mutant Kras and stromal cues, providing insight into the role of the tumor microenvironment in the origin and treatment of Ras-driven tumors.pancreatic ductal adenocarcinoma | tumor microenvironment | cancer metabolism | BRD2 | histone acetylation

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Section: Discussionmentioning

confidence: 99%

Stromal cues regulate the pancreatic cancer epigenome and metabolome

Sherman

Tseng

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

131

112

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“…PHLPP2, a phosphatase essential for specific and effective termination of oncogenic AKT signaling, was identified as a target gene of miR-181a in the current study [20,21]. PHLPP2, a tumor suppressor that inhibits cell growth and induces apoptosis in cancer cell lines [15], is located at 16q22.3, a region that undergoes loss of heterozygosity (LOH) in breast and ovarian cancers, prostate cancer, and hepatocellular carcinoma [22].…”

Section: Discussionmentioning

confidence: 91%

MiR-181a Targets PHLPP2 to Augment AKT Signaling and Regulate Proliferation and Apoptosis in Human Keloid Fibroblasts

Rang

Wang

Pang

et al. 2016

Cell Physiol Biochem

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Background/Aims: Keloids are fibrous overgrowths induced by cutaneous injury. MicroRNAs (miRNAs) have recently emerged as post-transcriptional gene repressors and participants in a diverse array of pathophysiological processes leading to skin disease. The purpose of the current study was to explore the precise functions of miR-181a in human keloid development and the underlying mechanisms. Methods: A miRNA microarray analysis was performed to compare expression profiles between keloid and normal skin tissues. Quantitative real-time PCR was conducted to estimate miR-181a expression. Cell proliferation was determined using the cell counting kit-8 (CCK-8) and 5-ethynyl-2-deoxyuridine (EdU) assays, and cell cycle and apoptosis were detected with flow cytometry. Direct targets of miR-181a were identified using the luciferase reporter assay. Results: miR-181a was significantly upregulated in human keloid tissues and fibroblasts, compared with their control counterparts. Overexpression of miR-181a enhanced keloid fibroblast DNA synthesis and proliferation and inhibited apoptosis, whereas miR-181a suppression triggered the opposite effects. Moreover, miR-181a suppressed the expression of PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2) through direct interactions with its 3′UTR region and subsequently enhanced AKT activation. Overexpression of PHLPP2 without its 3′UTR attenuated the effects of miR-181a on cell proliferation and apoptosis in keloid fibroblast cells. Furthermore, miR-181a mimics increased normal skin fibroblast proliferation. Conclusions: Our results highlight a novel pathway mediated by miR-181a, which may be effectively used as a therapeutic target for treatment of keloids.

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“…Several studies have suggested that IL-6 is a key mediator of the development of metastatic potential in cancer cells (25,26). Previous studies have indicated that IL-6 promotes the initial steps of cancer metastasis, potentially by upregulating MMP-9 through the PI3K/Akt signal pathway (27,28), and it has been demonstrated that IL-6 induces EMT through the expression of molecular markers (29,30). Therefore, the present study evaluated the expression of the primary biomarkers of EMT using western blotting and RT-PCR in SGC7901 cells treated with IL-6.…”

Section: Discussionmentioning

confidence: 99%

PIAS1 inhibited the metastasis of gastric cancer cell by epithelial-mesenchymal transition regulation within the inflammatory microenvironment

Wang

et al. 2018

Oncol Lett

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Abstract. Protein inhibitor of activated signal transducer and activator of transcription-1 (PIAS1) is an important regulator of the inflammatory signaling network, the expression of which was decreased in gastric cancer and implicated in the development of cancer. However, its mechanism has not been elucidated. The aim of the present study was to investigate the effect of PIAS1 on epithelial-mesenchymal transition (EMT) of gastric cancer cells within the inflammatory microenvironment. Recombinant adenovirus Ad5/F35-PIASl and Ad5/F35-null plasmids were constructed to transfect SGC7901 cells. Subsequently, these plasmids were confirmed by reverse transcription polymerase chain reaction and western blotting. The cells were treated with IL-6 or Ad5/F35-PIASl+IL-6, and the control cells were treated with Ad5/F35-null+IL-6. The morphological changes to the cells were observed using inverted microscopy. The effect of PIAS1 on cell migration and invasion was evaluated by scratch wound healing and Transwell chamber assays, and the protein expression of EMT markers and phosphatidylinositol 3-kinase (PI3K)/serine/threonine-protein kinase (Akt)/matrix metalloproteinase (MMP)-9 signaling pathway was examined by western blotting. Transfection with Ad5/F35-PIASl markedly increased the PIAS1 expression in SGC7901 cells. The cells acquired the more typical spindle-shape phenotype of mesenchymal cells following co-culture with IL-6; the cells co-cultured with IL-6 and Ad5/F35-PIASl acquired changes concordant with an epithelial phenotype. The overexpression of PIAS1 significantly decreased the migratory and invasive capacities of the SGC7901 cells (P<0.01). Western blotting indicated that the expression levels of E-cadherin protein in the cells treated with Ad5/F35-PIASl+IL-6 were increased significantly and the expression levels of zinc finger protein SNAI, Twist-related protein 1, vimentin and MMP-9, and the activation of PI3K/Akt proteins were decreased when compared with IL-6-or Ad5/F35-null+IL-6-treated cells (both P<0.01). PIAS1 may inhibit EMT in gastric cancer cells within the inflammatory microenvironment via the regulation of PI3K/Akt pathway activation, and may serve an important role in the inhibition of tumor invasion and metastasis with in this microenvironment. IntroductionGastric cancer is a common disease and a leading cause of cancer-associated mortality. According to a statistical study, ~70% of patients with gastric cancer in 2006 had lymph node metastasis at the time of diagnosis, leading to a median overall survival time of 16.7 months (1). Despite the standardization of surgical techniques and multimodal therapy, the postoperative survival of patients with advanced gastric cancer remains low in China due to the rates of invasion and metastasis (2).Epithelial-mesenchymal transition (EMT) is a process by which cells lose epithelial characteristics and acquire mesenchymal properties, including the loss of all cell-cell contact, increased motility and invasion (3). Previous studies have indicated that the EMT ...

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MYC Drives Pten/Trp53-Deficient Proliferation and Metastasis due to IL6 Secretion and AKT Suppression via PHLPP2

Cited by 73 publications

References 58 publications

Stromal cues regulate the pancreatic cancer epigenome and metabolome

Stromal cues regulate the pancreatic cancer epigenome and metabolome

MiR-181a Targets PHLPP2 to Augment AKT Signaling and Regulate Proliferation and Apoptosis in Human Keloid Fibroblasts

PIAS1 inhibited the metastasis of gastric cancer cell by epithelial-mesenchymal transition regulation within the inflammatory microenvironment

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