Loss of HIF1A From Pancreatic Cancer Cells Increases Expression of PPP1R1B and Degradation of p53 to Promote Invasion and Metastasis

Tiwari, Ashutosh; Tashiro, Kojiro; Dixit, Ajay Kumar; Soni, Aditi; Vogel, Keianna; Hall, Brad; Shafqat, Iram; Slaughter, Joseph R.; Param, Nesteen; Le, An K.; Saunders, Emily; Paithane, Utkarsha; Garcia, Guillermina; Campos, Alexandre Rosa; Zettervall, Jon; Carlson, Marjorie; Starr, Timothy K.; Marahrens, York; Deshpande, Aniruddha J.; Commisso, Cosimo; Provenzano, Paolo P.; Bagchi, Anindya

doi:10.1053/j.gastro.2020.07.046

Cited by 97 publications

(63 citation statements)

References 60 publications

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“…Combined with the result from the STRING database, we focused on the function of p53 at the follow-up study. It is known that tumor suppressor p53 involved in a variety of cellular events, for instance, p53/p21 signaling could induce cell cycle arrest and apoptosis as well as repress cell proliferation; oncogenes could promote MDM2-mediated degradation and ubiquitination of p53 [18][19][20][21][22][23][24][25][26][27][28][29]. In our study, we con rmed that the knockdown of PNO1 could increase luciferase activity by a p53-driven luciferase reporter assay and could enhance the protein levels of p53, CDKN1A (p21) and MDM2.…”

Section: Discussionsupporting

confidence: 59%

PNO1 promotes human cholangiocarcinoma tumorigenesis and chemosensitivity

Chen

Huang

et al. 2021

Preprint

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Background The partner of NOB1 homolog (PNO1) is important for ribosome biogenesis and serves as an oncogene in several cancers. However, the role of PNO1 in cholangiocarcinoma (CHOL) remains largely unknown. Methods The method of mRNA microarray analysis, high-throughput screening technologies, on-line databases analysis, PDXs models, biochemistry and molecular biology have been utilized to reveal the role of PNO1 in the progression of CHOL. Results PNO1 was significantly upregulated in CHOL tissues and predicted poor prognosis. PNO1 could induce cell proliferation and metastasis in vitro and in vivo. In CHOL cells expressing wild-type p53, PNO1 knockdown increased expression of p53 and its downstream gene p21 and decreased cell viability; these effects were blocked by p53 knockout and attenuated by the p53 inhibitor PFT-a. Furthermore, PNO1 knockdown reduced global protein synthesis and inhibiting MDM2-mediated ubiquitination and p53 degradation. Moreover, PNO1 overexpression enhanced the sensitivity to bortezomib treatment in CHOL. In addition, MYC overexpression promoted PNO1 promoter activity while MYC knockdown decreased PNO1 mRNA and protein, which led to decreased cell viability and clone formation. The expression of MYC was found positively correlated with PNO1 in CHOL patients. Conclusions Collectively, upregulation of PNO1 by MYC promotes cholangiocarcinoma tumorigenesis through suppressing p53 signaling pathway and enhanced the sensitivity to bortezomib treatment. PNO1 serves as a candidate of therapeutic target in CHOL treatment and clinical chemotherapy regimen.

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Section: Discussionsupporting

confidence: 59%

PNO1 promotes human cholangiocarcinoma tumorigenesis and chemosensitivity

Chen

Huang

et al. 2021

Preprint

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“…Deficiency of HIF-1α in PC cells enhances the expression of protein phosphatase 1 regulatory inhibitor subunit 1B (PPP1R1B), leading to phosphorylation of E3 ubiquitin-protein ligase (MDM2) at Ser166 and subsequent degradation of the p53 tumor suppressor protein. Loss of residual p53 significantly increases the metastatic potential of PC cells [ 152 ]. Moreover, genetic deletion of pancreas-specific HIF-1α drastically accelerates Kras G12D -driven PDAC neoplasia by enhancing B lymphocyte infiltration, indicating a protective role of HIF-1α in PC initiation [ 153 ].…”

Section: Introductionmentioning

confidence: 99%

“…Clinically, it was also demonstrated that weak HIF-1α expression correlates with poor prognosis in resectable PC and is an independent prognostic factor for PDAC-specific deaths [ 154 ]. From this perspective, the roles of HIF-1α in PC seem to be context dependent [ 152 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting hypoxic tumor microenvironment in pancreatic cancer

et al. 2021

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Attributable to its late diagnosis, early metastasis, and poor prognosis, pancreatic cancer remains one of the most lethal diseases worldwide. Unlike other solid tumors, pancreatic cancer harbors ample stromal cells and abundant extracellular matrix but lacks vascularization, resulting in persistent and severe hypoxia within the tumor. Hypoxic microenvironment has extensive effects on biological behaviors or malignant phenotypes of pancreatic cancer, including metabolic reprogramming, cancer stemness, invasion and metastasis, and pathological angiogenesis, which synergistically contribute to development and therapeutic resistance of pancreatic cancer. Through various mechanisms including but not confined to maintenance of redox homeostasis, activation of autophagy, epigenetic regulation, and those induced by hypoxia-inducible factors, intratumoral hypoxia drives the above biological processes in pancreatic cancer. Recognizing the pivotal roles of hypoxia in pancreatic cancer progression and therapies, hypoxia-based antitumoral strategies have been continuously developed over the recent years, some of which have been applied in clinical trials to evaluate their efficacy and safety in combinatory therapies for patients with pancreatic cancer. In this review, we discuss the molecular mechanisms underlying hypoxia-induced aggressive and therapeutically resistant phenotypes in both pancreatic cancerous and stromal cells. Additionally, we focus more on innovative therapies targeting the tumor hypoxic microenvironment itself, which hold great potential to overcome the resistance to chemotherapy and radiotherapy and to enhance antitumor efficacy and reduce toxicity to normal tissues.

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“…Intracellular calcium signaling in pancreatic duct cells is an important regulator of homeostatic bicarbonate secretion (19). PPP1R1B , SMARCA4 , and TGFB1 have well described roles in the pathogenesis of pancreatic cancer (20–22). We observed expression of markers of cluster 1, Anxa3 and Pah , which are also DEGs in cluster 4, to have cytoplasmic expression in all mouse and human pancreatic duct types (Figure S3A-B and Table S1).…”

Section: Resultsmentioning

confidence: 99%

Single cell transcriptome analysis defines heterogeneity of the murine pancreatic ductal tree

Hendley

Leonhardt

et al. 2020

Preprint

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Lineage tracing using genetically engineered mouse models is an essential tool for investigating cell-fate decisions of progenitor cells and biology of mature cell types, with relevance to physiology and disease progression. To study disease development, an inventory of an organ's cell types and understanding of physiologic function is paramount. Here, we performed single-cell RNA sequencing to examine heterogeneity of murine pancreatic duct cells, pancreatobiliary cells, and intrapancreatic bile duct cells. We isolated duct cells within the murine pancreas using a Dolichos biflorus agglutinin (DBA) lectin sorting strategy that labels all pancreatic duct cell types. Our data suggested the substructure of murine pancreatic duct cells is compartmentalized into three subpopulations. We describe an epithelial-mesenchymal transitory axis in our three pancreatic duct subpopulations and identify SPP1 as a regulator of this fate decision as well as human duct cell de-differentiation. Our results further identify functional heterogeneity within pancreatic duct subpopulations by elucidating a role for Geminin in accumulation of DNA damage in the setting of chronic pancreatitis. Our findings implicate diverse functional roles for subpopulations of pancreatic duct cells in maintenance of duct cell identity and disease progression and establish a comprehensive road map of murine pancreatic duct cell, pancreatobiliary cell, and intrapancreatic bile duct cell homeostasis.

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Loss of HIF1A From Pancreatic Cancer Cells Increases Expression of PPP1R1B and Degradation of p53 to Promote Invasion and Metastasis

Cited by 97 publications

References 60 publications

PNO1 promotes human cholangiocarcinoma tumorigenesis and chemosensitivity

PNO1 promotes human cholangiocarcinoma tumorigenesis and chemosensitivity

Targeting hypoxic tumor microenvironment in pancreatic cancer

Single cell transcriptome analysis defines heterogeneity of the murine pancreatic ductal tree

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