Publications by authors named "Wenwei Hu"

118 Publications

Tumor suppressor p53 regulates intestinal type 2 immunity.

Nat Commun 2021 06 7;12(1):3371. Epub 2021 Jun 7.

Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA.

The role of p53 in tumor suppression has been extensively studied and well-established. However, the role of p53 in parasitic infections and the intestinal type 2 immunity is unclear. Here, we report that p53 is crucial for intestinal type 2 immunity in response to the infection of parasites, such as Tritrichomonas muris and Nippostrongylus brasiliensis. Mechanistically, p53 plays a critical role in the activation of the tuft cell-IL-25-type 2 innate lymphoid cell circuit, partly via transcriptional regulation of Lrmp in tuft cells. Lrmp modulates Ca influx and IL-25 release, which are critical triggers of type 2 innate lymphoid cell response. Our results thus reveal a previously unrecognized function of p53 in regulating intestinal type 2 immunity to protect against parasitic infections, highlighting the role of p53 as a guardian of immune integrity.
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http://dx.doi.org/10.1038/s41467-021-23587-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184793PMC
June 2021

Clinical characteristics and prognostic value of the mutation in Chinese colorectal cancer patients.

Int J Biol Markers 2021 May 27:17246008211017152. Epub 2021 May 27.

Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China.

Background: The mutations are high-frequency somatic mutations found in colorectal cancer patients from Western and Asian countries however, with the exception of exon 2 of , other prevalence and prognostic values have not been adequately assessed in Asian patients. The aim of this study was to determine the mutation frequencies of whole exon mutations of in Chinese colorectal cancer patients and to investigate their impact on prognosis.

Methods: A total of 7189 tumor tissue samples (iCohort) were subjected to next-generation sequencing for detection of mutations. All pathologic or likely pathologic mutations of were considered. In addition, clinical features and prognostic dates were collected from 145 patients at The Third Affiliated Hospital of Soochow University, China (sCohort) and used droplet digital™ polymerase chain reaction to detect mutations.

Results: In the iCohort, 2706 patients (37.6%) were confirmed harboring mutations. The most frequent of these mutations were (32.19%), (17.96%), and (17.59%). In the sCohort, 51 colorectal cancer patients (35.17%) had mutations, among which (64.71%), (29.41%), and (3.92%) were high-frequency. The mutations were associated with shorter median overall survival than wild-type tumors (69 vs. 55 months; HR 1.80; 95% Cl 1.22, 2.64; =0.0003). In the Cox multivariate analysis, age (HR 1.562; 95% Cl 1.10, 2.22; =0.013), tumor differentiation (HR 0.417; 95% Cl 0.19, 0.90; =0.026), and mutation (HR 1.897; 95% Cl 0.19, 0.90; =0.001) remained independent predictors of shorter overall survival. Among the common mutations, was significantly associated with shorter overall survival (HR 2.17; 95% Cl 1.31, 3.58; < 0.0001) compared with wild-type patients.

Conclusions: Our findings indicate that KRAS genes are frequently mutated, and over 30% harbored the mutation subtype. We found that the mutation is associated with inferior survival and is a biomarker of poor prognosis in Chinese patients. Our data emphasize the importance of molecular features in colorectal cancer patients, which could potentially be improved by -specific related inhibitors.
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http://dx.doi.org/10.1177/17246008211017152DOI Listing
May 2021

The Interplay Between Tumor Suppressor p53 and Hypoxia Signaling Pathways in Cancer.

Front Cell Dev Biol 2021 18;9:648808. Epub 2021 Feb 18.

Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers-State University of New Jersey, New Brunswick, NJ, United States.

Hypoxia is a hallmark of solid tumors and plays a critical role in different steps of tumor progression, including proliferation, survival, angiogenesis, metastasis, metabolic reprogramming, and stemness of cancer cells. Activation of the hypoxia-inducible factor (HIF) signaling plays a critical role in regulating hypoxic responses in tumors. As a key tumor suppressor and transcription factor, p53 responds to a wide variety of stress signals, including hypoxia, and selectively transcribes its target genes to regulate various cellular responses to exert its function in tumor suppression. Studies have demonstrated a close but complex interplay between hypoxia and p53 signaling pathways. The p53 levels and activities can be regulated by the hypoxia and HIF signaling differently depending on the cell/tissue type and the severity and duration of hypoxia. On the other hand, p53 regulates the hypoxia and HIF signaling at multiple levels. Many tumor-associated mutant p53 proteins display gain-of-function (GOF) oncogenic activities to promote cancer progression. Emerging evidence has also shown that GOF mutant p53 can promote cancer progression through its interplay with the hypoxia and HIF signaling pathway. In this review, we summarize our current understanding of the interplay between the hypoxia and p53 signaling pathways, its impact upon cancer progression, and its potential application in cancer therapy.
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http://dx.doi.org/10.3389/fcell.2021.648808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930565PMC
February 2021

Correction to: A novel protein encoded by a circular RNA circPPP1R12A promotes tumor pathogenesis and metastasis of colon cancer via Hippo-YAP signaling.

Mol Cancer 2021 Feb 25;20(1):42. Epub 2021 Feb 25.

Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, People's Republic of China.

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http://dx.doi.org/10.1186/s12943-021-01337-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905669PMC
February 2021

Genetic and stochastic influences upon tumor formation and tumor types in Li-Fraumeni mouse models.

Life Sci Alliance 2021 03 29;4(3). Epub 2020 Dec 29.

Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, New Brunswick, NJ, USA

is the most frequently mutated gene in human cancers. Li-Fraumeni syndrome patients inheriting heterozygous mutations often have a much-increased risk to develop cancer(s) at early ages. Recent studies suggest that some individuals inherited mutations do not have the early onset or high frequency of cancers. These observations suggest that other genetic, environmental, immunological, epigenetic, or stochastic factors modify the penetrance of the cancerous mutant Tp53 phenotype. To test this possibility, this study explored dominant genetic modifiers of mutations in heterozygous mice with different genetic backgrounds. Both genetic and stochastic effects upon tumor formation were observed in these mice. The genetic background of mice carrying mutations has a strong influence upon the tissue type of the tumor produced and the number of tumors formed in a single mouse. The onset age of a tumor is correlated with the tissue type of that tumor, although identical tumor tissue types can occur at very different ages. These observations help to explain the great diversity of cancers in different Li-Fraumeni patients over lifetimes.
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http://dx.doi.org/10.26508/lsa.202000952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772779PMC
March 2021

The emerging role of leukemia inhibitory factor in cancer and therapy.

Pharmacol Ther 2021 May 28;221:107754. Epub 2020 Nov 28.

Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers-State University of New Jersey, New Brunswick, NJ 08903, USA. Electronic address:

Leukemia inhibitory factor (LIF) is a multi-functional cytokine of the interleukin-6 (IL-6) superfamily. Initially identified as a factor that inhibits the proliferation of murine myeloid leukemia cells, LIF displays a wide variety of important functions in a cell-, tissue- and context-dependent manner in many physiological and pathological processes, including regulating cell proliferation, pluripotent stem cell self-renewal, tissue/organ development and regeneration, neurogenesis and neural regeneration, maternal reproduction, inflammation, infection, immune response, and metabolism. Emerging evidence has shown that LIF plays an important but complex role in human cancers; while LIF displays a tumor suppressive function in some types of cancers, including leukemia, LIF is overexpressed and exerts an oncogenic function in many more types of cancers. Further, targeting LIF has been actively investigated as a novel strategy for cancer therapy. This review summarizes the recent advances in the studies on LIF in human cancers and its potential application in cancer therapy. A better understanding of the role of LIF in different types of cancers and its underlying mechanisms will help to develop more effective strategies for cancer therapy.
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http://dx.doi.org/10.1016/j.pharmthera.2020.107754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084904PMC
May 2021

The Regulation of Ferroptosis by Tumor Suppressor p53 and its Pathway.

Int J Mol Sci 2020 Nov 9;21(21). Epub 2020 Nov 9.

Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers-State University of New Jersey, New Brunswick, NJ 08903, USA.

Tumor suppressor p53 plays a key role in tumor suppression. In addition to tumor suppression, p53 is also involved in many other biological and pathological processes, such as immune response, maternal reproduction, tissue ischemia/reperfusion injuries and neurodegenerative diseases. While it has been widely accepted that the role of p53 in regulation of cell cycle arrest, senescence and apoptosis contributes greatly to the function of p53 in tumor suppression, emerging evidence has implicated that p53 also exerts its tumor suppressive function through regulation of many other cellular processes, such as metabolism, anti-oxidant defense and ferroptosis. Ferroptosis is a unique iron-dependent form of programmed cell death driven by lipid peroxidation in cells. Ferroptosis has been reported to be involved in cancer, tissue ischemia/reperfusion injuries and neurodegenerative diseases. Recent studies have shown that ferroptosis can be regulated by p53 and its signaling pathway as well as tumor-associated mutant p53. Interestingly, the regulation of ferroptosis by p53 appears to be highly context-dependent. In this review, we summarize recent advances in the regulation of ferroptosis by p53 and its signaling pathway. Further elucidation of the role and molecular mechanism of p53 in ferroptosis regulation will yield new therapeutic strategies for cancer and other diseases, including neurodegenerative diseases and tissue ischemia/reperfusion injuries.
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http://dx.doi.org/10.3390/ijms21218387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664917PMC
November 2020

Gain-of-function mutant p53 in cancer progression and therapy.

J Mol Cell Biol 2020 09;12(9):674-687

Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers-State University of New Jersey, New Brunswick, NJ 08903, USA.

p53 is a key tumor suppressor, and loss of p53 function is frequently a prerequisite for cancer development. The p53 gene is the most frequently mutated gene in human cancers; p53 mutations occur in >50% of all human cancers and in almost every type of human cancers. Most of p53 mutations in cancers are missense mutations, which produce the full-length mutant p53 (mutp53) protein with only one amino acid difference from wild-type p53 protein. In addition to loss of the tumor-suppressive function of wild-type p53, many mutp53 proteins acquire new oncogenic activities independently of wild-type p53 to promote cancer progression, termed gain-of-function (GOF). Mutp53 protein often accumulates to very high levels in cancer cells, which is critical for its GOF. Given the high mutation frequency of the p53 gene and the GOF activities of mutp53 in cancer, therapies targeting mutp53 have attracted great interest. Further understanding the mechanisms underlying mutp53 protein accumulation and GOF will help develop effective therapies treating human cancers containing mutp53. In this review, we summarize the recent advances in the studies on mutp53 regulation and GOF as well as therapies targeting mutp53 in human cancers.
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http://dx.doi.org/10.1093/jmcb/mjaa040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749743PMC
September 2020

LIF is essential for ISC function and protects against radiation-induced gastrointestinal syndrome.

Cell Death Dis 2020 07 27;11(7):588. Epub 2020 Jul 27.

Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, 08903, NJ, USA.

Leukemia inhibitory factor (LIF) is a cytokine essential for maintaining pluripotency of mouse embryonic stem cells. However, its role in adult intestinal stem cells (ISCs) is unclear. The adult intestinal epithelium has a high self-renewal rate driven by ISCs in crypts. Here, we find that LIF is present in the ISC niche in crypts and critical for the function of ISCs in maintaining the intestinal epithelial homeostasis and regeneration. Mechanistically, LIF maintains β-catenin activity through the AKT/GSK3β signaling to regulate ISC functions. LIF deficiency in mice impairs the renewal of the intestinal epithelium under the physiological condition. Further, LIF deficiency in mice impairs the regeneration of intestinal epithelium in response to radiation and shortens the lifespan of mice after high doses of radiation due to gastrointestinal (GI) syndrome, which can be rescued by administering recombinant LIF (rLIF). Importantly, LIF exhibits a radioprotective role in wild-type (WT) mice by protecting mice from lethal radiation-induced GI syndrome; administering rLIF promotes intestinal epithelial regeneration and prolongs survival in WT mice after radiation. These results reveal a previously unidentified and a crucial role of LIF in ensuring ISC function, promoting regeneration of the intestinal epithelium in response to radiation and protecting against radiation-induced GI syndrome.
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http://dx.doi.org/10.1038/s41419-020-02790-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385639PMC
July 2020

Elevating EGFR-MAPK program by a nonconventional Cdc42 enhances intestinal epithelial survival and regeneration.

JCI Insight 2020 08 20;5(16). Epub 2020 Aug 20.

Department of Biological Sciences, Division of Life Sciences, School of Arts and Sciences, Rutgers University, Newark, New Jersey, USA.

The regulatory mechanisms enabling the intestinal epithelium to maintain a high degree of regenerative capacity during mucosal injury remain unclear. Ex vivo survival and clonogenicity of intestinal stem cells (ISCs) strictly required growth response mediated by cell division control 42 (Cdc42) and Cdc42-deficient enteroids to undergo rapid apoptosis. Mechanistically, Cdc42 engaging with EGFR was required for EGF-stimulated, receptor-mediated endocytosis and sufficient to promote MAPK signaling. Proteomics and kinase analysis revealed that a physiologically, but nonconventionally, spliced Cdc42 variant 2 (V2) exhibited stronger MAPK-activating capability. Human CDC42-V2 is transcriptionally elevated in some colon tumor tissues. Accordingly, mice engineered to overexpress Cdc42-V2 in intestinal epithelium showed elevated MAPK signaling, enhanced regeneration, and reduced mucosal damage in response to irradiation. Overproducing Cdc42-V2 specifically in mouse ISCs enhanced intestinal regeneration following injury. Thus, the intrinsic Cdc42-MAPK program is required for intestinal epithelial regeneration, and elevating this signaling cascade is capable of initiating protection from genotoxic injury.
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http://dx.doi.org/10.1172/jci.insight.135923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455142PMC
August 2020

Parkin ubiquitinates phosphoglycerate dehydrogenase to suppress serine synthesis and tumor progression.

J Clin Invest 2020 06;130(6):3253-3269

Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, New Jersey, USA.

Phosphoglycerate dehydrogenase (PHGDH), the first rate-limiting enzyme of serine synthesis, is frequently overexpressed in human cancer. PHGDH overexpression activates serine synthesis to promote cancer progression. Currently, PHGDH regulation in normal cells and cancer is not well understood. Parkin, an E3 ubiquitin ligase involved in Parkinson's disease, is a tumor suppressor. Parkin expression is frequently downregulated in many types of cancer, and its tumor-suppressive mechanism is poorly defined. Here, we show that PHGDH is a substrate for Parkin-mediated ubiquitination and degradation. Parkin interacted with PHGDH and ubiquitinated PHGDH at lysine 330, leading to PHGDH degradation to suppress serine synthesis. Parkin deficiency in cancer cells stabilized PHGDH and activated serine synthesis to promote cell proliferation and tumorigenesis, which was largely abolished by targeting PHGDH with RNA interference, CRISPR/Cas9 KO, or small-molecule PHGDH inhibitors. Furthermore, Parkin expression was inversely correlated with PHGDH expression in human breast cancer and lung cancer. Our results revealed PHGDH ubiquitination by Parkin as a crucial mechanism for PHGDH regulation that contributes to the tumor-suppressive function of Parkin and identified Parkin downregulation as a critical mechanism underlying PHGDH overexpression in cancer.
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http://dx.doi.org/10.1172/JCI132876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260041PMC
June 2020

Association of KRAS mutation with tumor deposit status and overall survival of colorectal cancer.

Cancer Causes Control 2020 Jul 11;31(7):683-689. Epub 2020 May 11.

Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.

Purpose: To examine associations of KRAS mutation with tumor deposit status and overall survival in colorectal cancer (CRC) patients.

Methods: This retrospective cohort study included patients with incidental CRC diagnosed during 2010-2014 and recorded statuses of KRAS and tumor deposit in the National Cancer Database of the USA. Multivariable logistic regression and time-varying Cox regression analyses were used.

Results: We included 45,761 CRC patients with KRAS status (24,027 [52.5%] men, 24,240 [53.0%] < 65 years old, 17,338 [37.9%] with KRAS mutation). Adjusted for microsatellite instability, age, pathologic stage and tumor grade, KRAS mutation (versus wild type) was associated with tumor deposit presence (odds ratio = 1.11, 95% CI 1.02-1.20). KRAS mutation was also linked to worse overall survival of CRC patients regardless of tumor deposit status (adjusted Hazard ratio [HR] = 1.20, 95% CI 1.07-1.33 for CRC with tumor deposits, and adjusted HR = 1.24, 95% CI 1.14-1.35 or CRC without) or tumor stage (adjusted HR = 1.32, 95% CI 1.14-1.54 for early-stage and adjusted HR = 1.18, 95% CI 1.10-1.27 for late-stage). Microsatellite instability was associated with better overall survival in CRC without tumor deposit (adjusted HR = 0.89, 95% CI 0.79-0.99), but not in CRC with tumor deposit (adjusted HR = 1.12, 95% CI 0.97-1.30).

Conclusion: KRAS mutation is independently associated with tumor deposit presence and a worse overall survival in CRC patients.
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http://dx.doi.org/10.1007/s10552-020-01313-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319095PMC
July 2020

Gain of function mutant p53 protein activates AKT through the Rac1 signaling to promote tumorigenesis.

Cell Cycle 2020 06 10;19(11):1338-1351. Epub 2020 Apr 10.

Rutgers Cancer Institute of New Jersey; Rutgers University , New Brunswick, NJ, USA.

Tumor suppressor p53 is the most frequently mutated gene in human cancer. Mutant p53 (mutp53) not only loses the tumor suppressive activity of wild type p53, but often gains new oncogenic activities to promote tumorigenesis, defined as mutp53 gain of function (GOF). While the concept of mutp53 GOF is well-established, its underlying mechanism is not well-understood. AKT has been suggested to be activated by mutp53 and contribute to mutp53 GOF, but its underlying mechanism is unclear. In this study, we found that the activation of the Rac1 signaling by mutp53 mediates the promoting effect of mutp53 on AKT activation. Blocking Rac1 signaling by RNAi or a Rac1 inhibitor can inhibit AKT activation by mutp53. Importantly, targeting Rac1/AKT can greatly compromise mutp53 GOF in tumorigenesis. Results from this study uncover a new mechanism for AKT activation in tumors, and reveal that activation of AKT by mutp53 the Rac1 signaling contributes to mutp53 GOF in tumorigenesis. More importantly, this study provides Rac1 and AKT as potential targets for therapy in tumors containing mutp53.
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http://dx.doi.org/10.1080/15384101.2020.1749790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469461PMC
June 2020

Autophagy promotes mammalian survival by suppressing oxidative stress and p53.

Genes Dev 2020 05 19;34(9-10):688-700. Epub 2020 Mar 19.

Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA.

Autophagy captures intracellular components and delivers them to lysosomes for degradation and recycling. Conditional autophagy deficiency in adult mice causes liver damage, shortens life span to 3 mo due to neurodegeneration, and is lethal upon fasting. As autophagy deficiency causes p53 induction and cell death in neurons, we sought to test whether p53 mediates the lethal consequences of autophagy deficiency. Here, we conditionally deleted ( hereafter) and/or the essential autophagy gene throughout adult mice. Compared with mice, the life span of mice was extended due to delayed neurodegeneration and resistance to death upon fasting. also suppressed apoptosis induced by p53 activator Nutlin-3, suggesting that autophagy inhibited p53 activation. To test whether increased oxidative stress in mice was responsible for p53 activation, was deleted in the presence or absence of the master regulator of antioxidant defense nuclear factor erythroid 2-related factor 2 (). mice died rapidly due to small intestine damage, which was not rescued by codeletion. Thus, limits p53 activation and p53-mediated neurodegeneration. In turn, NRF2 mitigates lethal intestine degeneration upon autophagy loss. These findings illustrate the tissue-specific roles for autophagy and functional dependencies on the p53 and NRF2 stress response mechanisms.
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http://dx.doi.org/10.1101/gad.335570.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197357PMC
May 2020

Visible-Light-Triggered Quantitative Oxidation of 9,10-Dihydroanthracene to Anthraquinone by O under Mild Conditions.

ChemSusChem 2020 Apr 28;13(7):1785-1792. Epub 2020 Feb 28.

National and Local Joint Engineering Laboratory for New Petro-chemical Materials and Fine Utilization of Resources, College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha, Hunan, 410081, P.R. China.

The development of mild and efficient processes for the selective oxygenation of organic compounds by molecular oxygen (O ) is key for the synthesis of oxygenates. This paper discloses an atom-efficient synthesis protocol for the photo-oxygenation of 9,10-dihydroanthracene (DHA) by O to anthraquinone (AQ), which could achieve quantitative AQ yield (100 %) without any extra catalysts or additives under ambient temperature and pressure. A yield of 86.4 % AQ was obtained even in an air atmosphere. Furthermore, this protocol showed good compatibility for the photo-oxidation of several other compounds with similar structures to DHA. From a series of control experiments, free-radical quenching, and electron paramagnetic resonance spin-trapping results, the photo-oxygenation of DHA was probably initiated by its photoexcited state DHA*, and the latter could activate O to a superoxide anion radical (O ) through the transfer of its electron. Subsequently, this photo-oxidation was gradually dominated by the oxygenated product AQ as an active photocatalyst obtained from the oxidation of DHA by O , and was accelerated with the rapid accumulation of AQ. The present photo-oxidation protocol is a good example of selective oxygenation based on the photoexcited substrate self-activated O , which complies well with green chemistry ideals.
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http://dx.doi.org/10.1002/cssc.201903549DOI Listing
April 2020

The Identification and Analysis of mRNA-lncRNA-miRNA Cliques From the Integrative Network of Ovarian Cancer.

Front Genet 2019 21;10:751. Epub 2019 Aug 21.

Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.

Ovarian cancer is one of the leading causes of cancer mortality in women. Since little clinical symptoms were shown in the early period of ovarian cancer, most patients were found in phases III-IV or with abdominal metastasis when diagnosed. The lack of effective early diagnosis biomarkers makes ovarian cancer difficult to screen. However, in essence, the fundamental problem is we know very little about the regulatory mechanisms during tumorigenesis of ovarian cancer. There are emerging regulatory factors, such as long noncoding RNAs (lncRNAs) and microRNAs (miRNAs), which have played important roles in cancers. Therefore, we analyzed the RNA-seq profiles of 407 ovarian cancer patients. An integrative network of 20,424 coding RNAs (mRNAs), 10,412 lncRNAs, and 742 miRNAs were construed with variance inflation factor (VIF) regression method. The mRNA-lncRNA-miRNA cliques were identified from the network and analyzed. Such promising cliques showed significant correlations with survival and stage of ovarian cancer and characterized the complex sponge regulatory mechanism, suggesting their contributions to tumorigenicity. Our results provided novel insights of the regulatory mechanisms among mRNAs, lncRNAs, and miRNAs and highlighted several promising regulators for ovarian cancer detection and treatment.
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http://dx.doi.org/10.3389/fgene.2019.00751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712160PMC
August 2019

The role of p53 in reproduction, an unexpected function for a tumor suppressor.

J Mol Cell Biol 2019 07;11(7):624-627

Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08903, USA.

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http://dx.doi.org/10.1093/jmcb/mjz072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735926PMC
July 2019

Prognostic significance of resident CD103CD8T cells in human colorectal cancer tissues.

Acta Histochem 2019 Jul 30;121(5):657-663. Epub 2019 May 30.

Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, China; Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, China. Electronic address:

The prognostic significance and clinical implications of resident CD103CD8T cells in human colorectal cancer tissues still remains largely unexplored. In our present study, we aimed to characterize the resident CD8T cells in human colorectal cancer tissues by using double staining of CD103 and CD8, and further evaluated the prognostic significance of resident CD8T cells in colorectal cancer. We found that the OS rate of the colorectal cancer patients with higher infiltration of CD8T cells, or with higher numbers of resident CD103CD8T cells, or with higher ratio of CD103CD8T cells over total CD8T cells in cancer tissues was significantly better than that of the patients with lower infiltration of CD8T cells, or with lower numbers of resident CD103CD8T cells, or with higher ratio of CD103CD8T cells over total CD8T cells in cancer tissues, respectively. Moreover, higher infiltration of CD8T cells in colorectal cancer tissues was significantly and inversely correlated with advanced TNM stage. Higher numbers of resident CD103CD8T cells in colorectal cancer tissues were significantly and inversely correlated with distant metastasis status. Higher ratio of CD103CD8T cells over total CD8T cells in colorectal cancer tissues was significantly and inversely correlated with age status. The COX model analysis demonstrated that higher infiltration of CD8T cells, higher numbers of resident CD103CD8T cells, or higher ratio of CD103CD8T cells over total CD8T cells in colorectal cancer tissues, could serve as independent prognostic predictors for colorectal cancer patients. Taken together, our present study demonstrated the density of tumor infiltrating CD8T cells or the numbers of resident CD103CD8T cells in colorectal tissues could be used as an important prognostic predictor for this malignancy.
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http://dx.doi.org/10.1016/j.acthis.2019.05.009DOI Listing
July 2019

Hsa_circ_0009361 acts as the sponge of miR-582 to suppress colorectal cancer progression by regulating APC2 expression.

Clin Sci (Lond) 2019 05 30;133(10):1197-1213. Epub 2019 May 30.

Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou 213003, People's Republic of China

Circular RNA (circRNA) plays an important role in the development of human malignant tumors. Recently, an increasing number of circRNAs have been identified and investigated in various tumors. However, the expression pattern and biological function of circRNAs in colorectal cancer (CRC) still remain largely unexplored. In the present study, hsa_circ_0009361 was significantly down-regulated in CRC tissues and cells. Low expression level of hsa_circ_0009361 promoted the proliferation, epithelial-mesenchymal transition (EMT), migration, and invasion of CRC cells. Hsa_circ_0009361 was identified as the sponge of miR-582 by fluorescence hybridization (FISH), RNA immunoprecipitation (RIP), and luciferase reporter assays. Overexpression of hsa_circ_0009361 up-regulated the expression of adenomatous polyposis coli 2 (APC2) and inhibited the activity of the Wnt/β-catenin pathway by competitively combining with miR-582. Exogenous miR-582 and APC2 interventions could reverse the multiple biological functions mediated by hsa_circ_0009361 in CRC cells. experiments also confirmed that hsa_circ_0009361 inhibited the growth and metastasis of CRC. Hsa_circ_0009361 acted as a tumor suppressive sponge of miR-582, which could up-regulate the expression of APC2, inhibit the Wnt/β-catenin signaling, and suppress the growth and metastasis of CRC. Collectively, the hsa_circ_0009361/miR-582/APC2 network could be employed as a potential therapeutic target for CRC patients.
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http://dx.doi.org/10.1042/CS20190286DOI Listing
May 2019

A novel protein encoded by a circular RNA circPPP1R12A promotes tumor pathogenesis and metastasis of colon cancer via Hippo-YAP signaling.

Mol Cancer 2019 03 29;18(1):47. Epub 2019 Mar 29.

Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, People's Republic of China.

Background: It has been well established that circular RNAs (circRNAs) play an important regulatory role during tumor progression. Recent studies have indicated that even though circRNAs generally regulate gene expression through miRNA sponges, they may encode small peptides in tumor pathogenesis. However, it remains largely unexplored whether circRNAs are involved in the tumorigenesis of colon cancer (CC).

Methods: The expression profiles of circRNAs in CC tissues were assessed by circRNA microarray. Quantitative real-time PCR, RNase R digestion assay and tissue microarray were used to confirm the existence and expression pattern of circPPP1R12A. The subcellular distribution of circPPP1R12A was analyzed by nuclear mass separation assay and fluorescence in situ hybridization (FISH). SDS-PAGE and LC/MS were employed to evaluate the protein-coding ability of circPPP1R12A. CC cells were stably transfected with lentivirus approach, and cell proliferation, migration and invasion, as well as tumorigenesis and metastasis in nude mice were assessed to clarify the functional roles of circPPP1R12A and its encoded protein circPPP1R12A-73aa. RNA-sequencing and Western blotting analysis were furthered employed to identify the critical signaling pathway regulated by circPPP1R12A-73aa.

Results: We firstly screened the expression profiles of human circRNAs in CC tissues and found that the expression of hsa_circ_0000423 (termed as circPPP1R12A) was significantly increased in CC tissues. We also found that circPPP1R12A was mostly localized in the cytoplasm of CC cells. Kaplan-Meier analysis showed that patients with higher levels of circPPP1R12A had a significantly shorter overall survival. By gain- and loss-of-function approaches, the results suggested that circPPP1R12A played a critical role in proliferation, migration and invasion of CC cells. Furthermore, we showed that circPPP1R12A carried an open reading frame (ORF), which encoded a functional protein (termed as circPPP1R12A-73aa). Next, we found that PPP1R12A-C, not circPPP1R12A, promoted the proliferation, migration and invasion abilities of CC in vitro and in vivo. Finally, we identified that circPPP1R12A-73aa promoted the growth and metastasis of CC via activating Hippo-YAP signaling pathway. In addition, the YAP specific inhibitor Peptide 17 dramatically alleviated the promotive effect of circPPP1R12A-73aa on CC cells.

Conclusions: In the present study, we illustrated the coding-potential of circRNA circPPP1R12A in the progression of CC. Moreover, we identified that circPPP1R12A-73aa promoted the tumor pathogenesis and metastasis of CC via activating Hippo-YAP signaling pathway. Our findings might provide valuable insights into the development of novel potential therapeutic targets for CC.
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http://dx.doi.org/10.1186/s12943-019-1010-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440158PMC
March 2019

miR-183-5p Inhibits Occurrence and Progression of Acute Myeloid Leukemia via Targeting Erbin.

Mol Ther 2019 03 1;27(3):542-558. Epub 2019 Feb 1.

Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China; Cancer Immunotherapy Engineering Research Center of Jiangsu Province, Changzhou, Jiangsu Province, China; Institute of Cell Therapy, Soochow University, Changzhou, Jiangsu Province, China. Electronic address:

Erbin has been shown to have significant effects on the development of solid tumors. However, little is known about its function and regulatory mechanism in hematological malignancies. The biological function of Erbin on cell proliferation was measured in vitro and in vivo. The predicted target of Erbin was validated by dual-luciferase reporter assay and rescue experiment. We found that overexpression of Erbin could inhibit the cell proliferation and promote the cell differentiation of acute myeloid leukemia (AML) cells, whereas depletion of Erbin could enhance the cell proliferation and block the cell differentiation in AML cells in vitro and in vivo. Besides, miR-183-5p was identified as the upstream regulator that negatively regulated the Erbin expression. The results were confirmed by dual-luciferase reporter and RNA pull-down assay. Furthermore, we found that miR-183-5p negatively regulated Erbin, resulting in enhanced cell proliferation of AML cells via activation of RAS/RAF/MEK/ERK and PI3K/AKT/FoxO3a pathways. The activation of RAS/RAF/MEK/ERK and PI3K/AKT/FoxO3a pathways was mediated by Erbin interacting with Grb2. These results were also validated by rescue experiments in vitro and in vivo. All above-mentioned findings indicated that the miR-183-5p/Erbin signaling pathway might represent a novel prognostic biomarker or therapeutic target for treatment of AML.
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http://dx.doi.org/10.1016/j.ymthe.2019.01.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401194PMC
March 2019

Tumor suppressor p53 and metabolism.

J Mol Cell Biol 2019 04;11(4):284-292

Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, State University of New Jersey, New Brunswick, NJ, USA.

p53 plays a key role in tumor suppression. The tumor suppressive function of p53 has long been attributed to its ability to induce apoptosis, cell cycle arrest, and senescence in cells. However, recent studies suggest that other functions of p53 also contribute to its role as a tumor suppressor, such as its function in metabolic regulation. p53 regulates various metabolic pathways to maintain the metabolic homeostasis of cells and adapt cells to stress. In addition, recent studies have also shown that gain-of-function (GOF) mutant p53 proteins drive metabolic reprogramming in cancer cells, contributing to cancer progression. Further understanding of p53 and its GOF mutants in metabolism will provide new opportunities for cancer therapy.
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http://dx.doi.org/10.1093/jmcb/mjy070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487777PMC
April 2019

IL-1β-Mediated Up-Regulation of WT1D via miR-144-3p and Their Synergistic Effect with NF-κB/COX-2/HIF-1α Pathway on Cell Proliferation in LUAD.

Cell Physiol Biochem 2018 17;48(6):2493-2502. Epub 2018 Aug 17.

Department of Oncology, the Third Affiliated Hospital of Soochow University, Changzhou, China.

Background/aims: IL-1β is an important mediator of "inflammation-cancer" transformation through IL-1β/NF-κB/COX-2/HIF-1α signaling pathway, whereas certain portion of patients with lung adenocarcinoma (LUAD) still suffer from rapid tumor progression in clinical practice, indicating the occurrence of potential bypass.

Methods: Real-time polymerase chain reaction was applied to examine the expressions of mir-144-3p, WT1, NF-κB, COX2 and HIF-1α at the mRNA level in 127 LUAD samples and corresponding adjacent tissues. miR-144-3p mimic and antagormiR were used to trigger activation and suppression of miR-144-3p in A549 cells, respectively. MTT assay and Western blotting analysis were carried out to evaluate the cell proliferation. Stable clones with over-expression or knockdown of WT1 were generated with plasmid or shRNA by lentiviral vector technology in H1568 and H1650 NSCLC cell lines, respectively. Dual luciferase reporter assay was performed to validate the effect of miR-144-3p on WT1D. Xenograft model was established for in vivo experiment, and TCGA data were extracted for validation.

Results: miR-144-3p could suppress the WT1D expression at the post-transcriptional level, hence regulating cell proliferation in LUAD. WT1 and COX-2 were independent prognostic factors of LUAD patients. In addition, inhibition of IL-1β/miR-144-3p/WT1D and IL-1β/NF-κB/COX-2/HIF-1α pathways using miR-144-3p mimic and Celecoxib, respectively, displayed synergistic suppressive effect on cell proliferation in LUAD.

Conclusion: A de novo IL-1β/miR-144-3p/WT1D axis was involved in proliferative regulation of LUAD. Moreover, simultaneous blockade of both IL-1β/miR-144-3p/WT1D and IL-1β/NF-κB/COX-2/ HIF-1α pathways might have synergistic suppressive effect on cell proliferation in LUAD.
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http://dx.doi.org/10.1159/000492687DOI Listing
September 2018

Parkinson's disease-associated protein Parkin: an unusual player in cancer.

Cancer Commun (Lond) 2018 06 26;38(1):40. Epub 2018 Jun 26.

Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, New Brunswick, NJ, 08903, USA.

The mutation of the Parkin gene is a cause of familial Parkinson's disease. A growing body of evidence suggests that Parkin also functions as a tumor suppressor. Parkin is an ubiquitin E3 ligase, and plays important roles in a variety of cellular processes implicated in tumorigenesis, including cell cycle, cell proliferation, apoptosis, metastasis, mitophagy and metabolic reprogramming. Here we review the role and mechanism of Parkin in cancer.
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http://dx.doi.org/10.1186/s40880-018-0314-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020249PMC
June 2018

Inhibition of HIV early replication by the p53 and its downstream gene p21.

Virol J 2018 03 27;15(1):53. Epub 2018 Mar 27.

Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, Albany, NY, 12208, USA.

Background: The tumor suppressor gene p53 has been found to suppress HIV infection by various mechanisms, but the inhibition of HIV at an early stage of replication by host cell p53 and its downstream gene p21 has not been well studied.

Method: VSV-G pseudotyped HIV-1 or HIV-2 viruses with GFP or luciferase reporter gene were used to infect HCT116 p53 cells, HCT116 p53 cells and hMDMs. The infections were detected by flow cytometry or measured by luciferase assay. Reverse transcription products were quantified by a TaqMan real time PCR. siRNA knockdown experiments were applied to study potential roles of p53 and p21 genes in their restriction to HIV infection. Western blot experiments were used to analyze changes in gene expression.

Results: The infection of HIV-1 was inhibited in HCT116 p53 cells in comparison to HCT116 p53 cells. The fold of inhibition was largely increased when cell cycle switched from cycling to non-cycling status. Further analysis showed that both p53 and p21 expressions were upregulated in non-cycling HCT116 p53 cells and HIV-1 reverse transcription was subsequently inhibited. siRNA knockdown of either p53 or p21 rescued HIV-1 reverse transcription from the inhibition in non-cycling HCT116 p53 cells. It was identified that the observed restrictions by p53 and p21 were associated with the suppression of RNR2 expression and phosphorylation of SAMHD1. These observations were confirmed by using siRNA knockdown experiments. In addition, p53 also inhibited HIV-2 infection in HCT116 p53 cells and siRNA knockdown of p21 increased HIV-2 infection in hMDMs. Finally the expressions of p53 and p21 were found to be induced in hMDMs shortly after HIV-1 infection.

Conclusions: The p53 and its downstream gene p21 interfere with HIV early stage of replication in non-cycling cells and hMDMs.
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http://dx.doi.org/10.1186/s12985-018-0959-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870690PMC
March 2018

A polymorphism in the tumor suppressor p53 affects aging and longevity in mouse models.

Elife 2018 03 20;7. Epub 2018 Mar 20.

Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, New Brunswick, United States.

Tumor suppressor p53 prevents early death due to cancer development. However, the role of p53 in aging process and longevity has not been well-established. In humans, single nucleotide polymorphism (SNP) with either arginine (R72) or proline (P72) at codon 72 influences p53 activity; the P72 allele has a weaker p53 activity and function in tumor suppression. Here, employing a mouse model with knock-in of human gene carrying codon 72 SNP, we found that despite increased cancer risk, P72 mice that escape tumor development display a longer lifespan than R72 mice. Further, P72 mice have a delayed development of aging-associated phenotypes compared with R72 mice. Mechanistically, P72 mice can better retain the self-renewal function of stem/progenitor cells compared with R72 mice during aging. This study provides direct genetic evidence demonstrating that p53 codon 72 SNP directly impacts aging and longevity, which supports a role of p53 in regulation of longevity.
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http://dx.doi.org/10.7554/eLife.34701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906094PMC
March 2018

Prognostic Role of Tumor-Infiltrating Lymphocytes in Esophagus Cancer: a Meta-Analysis.

Cell Physiol Biochem 2018 31;45(2):720-732. Epub 2018 Jan 31.

Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.

Background/aims: Several studies have verified the correlation between tumor-infiltrating lymphocytes (TILs) and survival of patients with esophagus cancer (EC). However, the prognostic role of TILs is still controversial. Therefore, we performed this meta-analysis.

Methods: We searched PubMed, Embase and the Cochrane Library (last update by August 30, 2017) to identify studies assessing the effect of TILs on survival of patients with EC. Pooled hazard ratios (HRs) for overall survival (OS), disease-free survival (DFS) and cancer specific survival (CSS) were estimated using fixed-effects models or random-effects models, which depends on the heterogeneity.

Results: Data from 22 observational studies including 2909 patients were summarized. Pooled analysis indicated that generalized TILs were favorable prognostic markers for OS in patients with EC (pooled HR = 0.48; 95% CI = 0.38-0.61; P < 0.001). For TIL subsets, CD8+ TILs were associated with improved OS (pooled HR = 0.68; 95% CI = 0.58-0.84; P < 0.001) and DFS (pooled HR = 0.90; 95% CI = 0.85-0.95; P < 0.001); FoxP3+ TILs were associated with patients' DFS (pooled HR = 0.88; 95% CI = 0.81-0.96; P = 0.003). High CD57+ TILs indicated a better OS in patients with EC (pooled HR = 0.50; 95% CI = 0.35-0.72; P < 0.001). In addition, the pooled results showed that other TIL subsets including CD3+, CD4+ and CD45RO+ TILs were not associated with patients' survival (P > 0.05).

Conclusions: For patients with EC, some TIL subsets could serve as prognostic biomarkers. The application of TILs in the immunotherapy of EC needs to be verified through a large amount of clinical research.
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http://dx.doi.org/10.1159/000487164DOI Listing
March 2018

Parkin targets HIF-1α for ubiquitination and degradation to inhibit breast tumor progression.

Nat Commun 2017 11 28;8(1):1823. Epub 2017 Nov 28.

Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers, State University of New Jersey, New Brunswick, NJ, 08903, USA.

Mutations in E3 ubiquitin ligase Parkin have been linked to familial Parkinson's disease. Accumulating evidence suggests that Parkin is a tumor suppressor, but the underlying mechanism is poorly understood. Here we show that Parkin is an E3 ubiquitin ligase for hypoxia-inducible factor 1α (HIF-1α). Parkin interacts with HIF-1α and promotes HIF-1α degradation through ubiquitination, which in turn inhibits metastasis of breast cancer cells. Parkin downregulation in breast cancer cells promotes metastasis, which can be inhibited by targeting HIF-1α with RNA interference or the small-molecule inhibitor YC-1. We further identify lysine 477 (K477) of HIF-1α as a major ubiquitination site for Parkin. K477R HIF-1α mutation and specific cancer-associated Parkin mutations largely abolish the functions of Parkin to ubiquitinate HIF-1α and inhibit cancer metastasis. Importantly, Parkin expression is inversely correlated with HIF-1α expression and metastasis in breast cancer. Our results reveal an important mechanism for Parkin in tumor suppression and HIF-1α regulation.
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http://dx.doi.org/10.1038/s41467-017-01947-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703960PMC
November 2017

MiR-629 promotes human pancreatic cancer progression by targeting FOXO3.

Cell Death Dis 2017 10 26;8(10):e3154. Epub 2017 Oct 26.

Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, P.R. China.

The FOXO signaling pathway has been reported to have an important role in human cancer. Expression of miR-629 was markedly upregulated in pancreatic cancer and negatively correlated with FOXO3. Therefore, exploring the regulatory mechanism of miR-629 and FOXO3 signaling may provide valuable clinical targets for pancreatic cancer therapy. In the current study, we found that overexpressing and inhibiting miR-629, respectively, enhanced and reduced the cell proliferation and metastasis of pancreatic cancer cells in vitro and in vivo compared with parental cells or cells transfected with a control vector. Furthermore, we found that miR-629 negatively regulated FOXO3 protein expression and decreased the activity of a luciferase reporter construct containing the FOXO3 3'-untranslated region. These results show that miR-629 regulates FOXO3 at the posttranscriptional level, resulting in enhanced cell proliferation and invasion of pancreatic carcinoma. Furthermore, we found that overexpressing miR-629 enhanced, while inhibiting miR-629 reduced, the stem cell-like phenotype of pancreatic cancer cells in vitro. A functional polymorphism at miR-629-binding site in the 3'-UTR of FOXO3 gene confers a decreased risk of progression in pancreatic carcinoma. Furthermore, these findings suggest that miR-629 has a vital role in promoting the development of pancreatic cancer and may represent a novel prognostic biomarker and therapeutic target.
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http://dx.doi.org/10.1038/cddis.2017.525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5682687PMC
October 2017