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1.
Mol Carcinog ; 62(3): 348-359, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36453714

RESUMEN

Adenosine-to-inosine (A-to-I) RNA editing is the most common posttranscriptional editing to create somatic mutations and increase proteomic diversity. However, the functions of the edited mutations are largely underexplored. To identify novel targets in lung adenocarcinoma (LUAD), we conducted a genome-wide somatic A-to-I RNA editing analysis of 23 paired adjacent normal and LUAD transcriptomes and identified 26,280 events, including known nonsynonymous AZIN1-S367G and novel RHOAiso2 (RHOA isoform 2)-R176G, tubulin gamma complex associated protein 2 (TUBGCP2)-N211S, and RBMXL1-I40 M mutations. We validated the edited mutations in silico in multiple databases and in newly collected LUAD tissue pairs with the SEQUENOM MassARRAY® and TaqMan PCR Systems. We selected RHOAiso2-R176G due to its significant level, isoform-specificity, and being the most common somatic edited nonsynonymous mutation of RHOAiso2 to investigate its roles in LUAD tumorigenesis. RHOAiso2 is a ubiquitous but low-expression alternative spliced isoform received a unique Alu-rich exon at the 3' RHOA mRNA to become an editing RNA target, leading to somatic hypermutation and protein diversity. Interestingly, LUAD patients harboring the RHOAiso2-R176G mutation were associated with aberrant RHOA functions, cancer cell proliferation and migration, and poor clinical outcomes in transcriptome analysis. Mechanistically, RHOAiso2-R176G mutation-expressing LUAD cells potentiate RHOA-guanosine triphosphate (GTP) activity to phosphorylate ROCK1/2 effectors and enhance cell proliferation and migration in vitro and increase tumor growth in xenograft and systemic metastasis models in vivo. Taken together, the RHOAiso2-R176G mutation is a common somatic A-to-I edited mutation of the hypermutated RHOA isoform 2. It is an oncogenic and isoform-specific theranostic target that activates RHOA-GTP/p-ROCK1/2 signaling to promote tumor progression.


Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , ARN , Proteómica , Adenosina , Adenocarcinoma del Pulmón/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Neoplasias Pulmonares/genética , Guanosina Trifosfato , Inosina , Mutación , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Proteína de Unión al GTP rhoA/genética , Proteína de Unión al GTP rhoA/metabolismo
2.
Nucleic Acids Res ; 48(3): 1175-1191, 2020 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-31853539

RESUMEN

Precise noncoding RNA (ncRNA)-based network prediction is necessary to reveal ncRNA functions and pathological mechanisms. Here, we established a systemic pipeline to identify prognostic ncRNAs, predict their functions and explore their pathological mechanisms in lung adenocarcinoma (LUAD). After in silico and experimental validation based on evaluations of prognostic value in multiple LUAD cohorts, we selected the PTTG3P pseudogene from among other prognostic ncRNAs (MIR497HG, HSP078, TBX5-AS1, LOC100506990 and C14orf64) for mechanistic studies. PTTG3P upregulation in LUAD cells shortens the metaphase to anaphase transition in mitosis, increases cell viability after cisplatin or paclitaxel treatment, facilitates tumor growth that leads to poor survival in orthotopic lung models, and is associated with a poor survival rate in LUAD patients in the TCGA cohort who received chemotherapy. Mechanistically, PTTG3P acts as an ncRNA that interacts with the transcription factor FOXM1 to regulate the transcriptional activation of the mitotic checkpoint kinase BUB1B, which augments tumor growth and chemoresistance and leads to poor outcomes for LUAD patients. Overall, we established a systematic strategy to uncover prognostic ncRNAs with functional prediction methods suitable for pan-cancer studies. Moreover, we revealed that PTTG3P, due to its upregulation of the PTTG3P/FOXM1/BUB1B axis, could be a therapeutic target for LUAD patients.


Asunto(s)
Adenocarcinoma/genética , Neoplasias Pulmonares/genética , ARN no Traducido/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Animales , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Proliferación Celular , Cromatina/genética , Simulación por Computador , Resistencia a Antineoplásicos/genética , Proteína Forkhead Box M1/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Ratones , Mitosis , Pronóstico , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal
3.
J Acquir Immune Defic Syndr ; 94(1): 73-81, 2023 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-37276242

RESUMEN

INTRODUCTION: Persons with HIV (PWH) experience high rates of human papillomavirus (HPV)-associated cancers compared with the general population. Plasma HPV cell-free DNA (cfDNA) tests are sensitive in patients with known HPV-associated cancers. It is not known whether these tests can screen for invasive cancers in populations with high burdens of nonmalignant HPV disease such as PWH. It was not known whether HPV infection and/or noninvasive anal high-grade squamous intraepithelial lesions (HSIL) alone in this population would result in detectable HPV cfDNA, which would result in a high number of false positives if HPV cfDNA is used to screen for invasive cancers. METHODS: We conducted a prospective study of PWH in 2 cohorts: 20 without anal HSIL and 20 with anal HSIL. We tested anal and vaginal swabs for HPV infection, and HPV genotyped the biopsies of anal HSIL. Finally, we performed HPV cfDNA droplet digital polymerase chain reaction to test for HPV16/18/33 from plasma samples. RESULTS: In the combined cohorts, the median age was 56 years, 12.5% were cisgender women, and none had detectable HIV. In total, 84.6% had prevalent anovaginal HPV infection, including 10 participants with HPV16, 13 with HPV18, and 2 with HPV33 infections. Five and 2 participants had HPV16 and HPV33 detected in anal HSIL, respectively. Despite the high prevalence of HPV infection and anal HSIL, no participant had HPV16/18/33 detectable cfDNA by droplet digital polymerase chain reaction. CONCLUSIONS: These results provide a strong rationale for investigating the use of HPV cfDNA in a screening setting for suspected HPV-related invasive cancers in PWH.


Asunto(s)
Neoplasias del Ano , Infecciones por VIH , Infecciones por Papillomavirus , Lesiones Intraepiteliales Escamosas , Humanos , Femenino , Persona de Mediana Edad , Virus del Papiloma Humano , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/epidemiología , Infecciones por VIH/complicaciones , Papillomavirus Humano 16 , Estudios Prospectivos , Papillomavirus Humano 18 , Neoplasias del Ano/epidemiología , Lesiones Intraepiteliales Escamosas/complicaciones , Papillomaviridae/genética , Prevalencia
4.
Comput Struct Biotechnol J ; 20: 1752-1763, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35495118

RESUMEN

With the increasing incidence and mortality of human hepatocellular carcinoma (HCC) worldwide, revealing innovative targets to improve therapeutic strategies is crucial for prolonging the lives of patients. To identify innovative targets, we conducted a comprehensive comparative transcriptome analysis of 5,410 human HCCs and 974 mouse liver cancers to identify concordantly expressed genes associated with patient survival. Among the 664 identified prognostic comparative HCC (pcHCC) genes, upregulated pcHCC genes were associated with prognostic clinical features, including large tumor size, vascular invasion and late HCC stages. Interestingly, after validating HCC patient prognoses in multiple independent datasets, we matched the 664 aberrant pcHCC genes with the sorafenib-altered genes in TCGA_LIHC patients and found these 664 pcHCC genes were enriched in sorafenib-related functions, such as downregulated xenobiotic and lipid metabolism and upregulated cell proliferation. Therapeutic agents targeting aberrant pcHCC genes presented divergent molecular mechanisms, including suppression of sorafenib-unrelated oncogenic pathways, induction of sorafenib-unrelated ferroptosis, and modulation of sorafenib transportation and metabolism, to potentiate sorafenib therapeutic effects in HCC combination therapy. Moreover, the pcHCC genes NCAPG and CENPW, which have not been targeted in combination with sorafenib treatment, were knocked down and combined with sorafenib treatment, which reduced HCC cell viability based on disruption to the p38/STAT3 axis, thereby hypersensitizing HCC cells. Together, our results provide important resources and reveal that 664 pcHCC genes represent innovative targets suitable for developing therapeutic strategies in combination with sorafenib based on the divergent synergistic mechanisms for HCC tumor suppression.

5.
Nat Commun ; 10(1): 5716, 2019 12 16.
Artículo en Inglés | MEDLINE | ID: mdl-31844057

RESUMEN

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide due to metastasis. Paraspeckle component 1 (PSPC1) upregulation has been identified as an HCC pro-metastatic activator associated with poor patient prognosis, but with a lack of targeting strategy. Here, we report that PSPC1, a nuclear substrate of PTK6, sequesters PTK6 in the nucleus and loses its metastasis driving capability. Conversely, PSPC1 upregulation or PSPC1-Y523F mutation promotes epithelial-mesenchymal transition, stemness, and metastasis via cytoplasmic translocation of active PTK6 and nuclear translocation of ß-catenin, which interacts with PSPC1 to augment Wnt3a autocrine signaling. The aberrant nucleocytoplasmic shuttling of active PTK6/ß-catenin is reversed by expressing the PSPC1 C-terminal interacting domain (PSPC1-CT131), thereby suppressing PSPC1/PTK6/ß-catenin-activated metastasis to prolong the survival of HCC orthotopic mice. Thus, PSPC1 is the contextual determinant of the oncogenic switch of PTK6/ß-catenin subcellular localizations, and PSPC1-CT131 functions as a dual inhibitor of PSPC1 and PTK6 with potential for improving cancer therapy.


Asunto(s)
Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Proteínas de Neoplasias/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Proteínas de Unión al ARN/metabolismo , beta Catenina/metabolismo , Adulto , Anciano , Animales , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidad , Línea Celular Tumoral , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal/genética , Femenino , Humanos , Estimación de Kaplan-Meier , Hígado/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidad , Masculino , Ratones , Persona de Mediana Edad , Mutación , Proteínas de Unión al ARN/genética , Transducción de Señal , Regulación hacia Arriba , Proteína Wnt3A/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Adulto Joven
6.
J Clin Invest ; 127(8): 2982-2997, 2017 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-28691927

RESUMEN

The tumor microenvironment plays an important role in tumor growth and metastasis. However, the mechanism by which tumor cells regulate the cell and non-cell constituents of surrounding stroma remains incompletely understood. Promyelocytic leukemia (PML) is a pleiotropic tumor suppressor, but its role in tumor microenvironment regulation is poorly characterized. PML is frequently downregulated in many cancer types, including lung cancer. Here, we identify a PML ubiquitination pathway that is mediated by WD repeat 4-containing cullin-RING ubiquitin ligase 4 (CRL4WDR4). Clinically, this PML degradation pathway is hyperactivated in lung cancer and correlates with poor prognosis. The WDR4/PML axis induces a set of cell-surface or secreted factors, including CD73, urokinase-type plasminogen activator receptor (uPAR), and serum amyloid A2 (SAA2), which elicit paracrine effects to stimulate migration, invasion, and metastasis in multiple lung cancer models. In xenograft and genetically engineered mouse models, the WDR4/PML axis elevates intratumoral Tregs and M2-like macrophages and reduces CD8+ T cells to promote lung tumor growth. These immunosuppressive effects were all reversed by CD73 blockade. Our study identifies WDR4 as an oncoprotein that negatively regulates PML via ubiquitination to promote lung cancer progression by fostering an immunosuppressive and prometastatic tumor microenvironment, suggesting the potential of immune-modulatory approaches for treating lung cancer with aberrant PML degradation.


Asunto(s)
Proteínas de Unión al GTP/metabolismo , Tolerancia Inmunológica , Leucemia Promielocítica Aguda/metabolismo , Proteína de la Leucemia Promielocítica/metabolismo , Microambiente Tumoral , Ubiquitinación , Células A549 , Animales , Línea Celular Tumoral , Movimiento Celular , Progresión de la Enfermedad , Células HEK293 , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Metástasis de la Neoplasia , Proteínas Nucleares/genética , Pronóstico , Interferencia de ARN , Proteínas Supresoras de Tumor/genética
7.
Int J Nanomedicine ; 11: 1687-700, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27217747

RESUMEN

Berberine (Brb) is an active alkaloid occurring in various common plant species, with well-recognized potential for cancer therapy. Brb not only augments the efficacy of antineoplastic chemotherapy and radiotherapy but also exhibits direct antimitotic and proapoptotic actions, along with distinct antiangiogenic and antimetastatic activities in a variety of tumors. Despite its low systemic toxicity, several pharmaceutical challenges limit the application of Brb in cancer therapy (ie, extremely low solubility and permeability, very poor pharmacokinetics (PKs), and oral bioavailability). Among lipid-based nanocarriers investigated recently for Brb, stealth amphiphilic micelles of polymeric phospholipid conjugates were studied here as a promising strategy to improve Brb delivery to tumors. Specifically, physicochemically stable micelles made of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (PEG-PE) mixed with d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) (PEG-succinate ester of vitamin E), in a 3:1 M ratio, increased Brb solubilization by 300%. Our PEG-PE/TPGS-mixed micelles firmly retained the incorporated Brb, displaying extended-release profile in simulated media, with up to 30-fold projected improvement in simulated PKs of Brb. Owing to the markedly better uptake of Brb-containing mixed micelles in vitro, our Brb-mixed micelles nanoformulation significantly amplified apoptosis and overall cytotoxic effectiveness against monolayer and spheroid cultures of human prostate carcinomas (16- to 18-fold lower half-maximal inhibitory concentration values in PC3 and LNPaC, respectively), compared to free Brb. Mixed PEG-PE/TPGS micelles represent a promising delivery platform for the sparingly soluble anticancer agent, Brb, encouraging further pharmaceutical development of this drug for cancer therapy.


Asunto(s)
Antineoplásicos/uso terapéutico , Berberina/uso terapéutico , Micelas , Nanopartículas/química , Fosfatidiletanolaminas/química , Polietilenglicoles/química , Vitamina E/uso terapéutico , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Berberina/química , Berberina/farmacología , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Colon/efectos de los fármacos , Liberación de Fármacos , Humanos , Solubilidad , Esferoides Celulares/efectos de los fármacos , Factores de Tiempo , Vitamina E/química , Vitamina E/farmacocinética , Vitamina E/farmacología
8.
J Clin Invest ; 122(8): 2884-97, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22820290

RESUMEN

MicroRNA-122 (miR-122), which accounts for 70% of the liver's total miRNAs, plays a pivotal role in the liver. However, its intrinsic physiological roles remain largely undetermined. We demonstrated that mice lacking the gene encoding miR-122a (Mir122a) are viable but develop temporally controlled steatohepatitis, fibrosis, and hepatocellular carcinoma (HCC). These mice exhibited a striking disparity in HCC incidence based on sex, with a male-to-female ratio of 3.9:1, which recapitulates the disease incidence in humans. Impaired expression of microsomal triglyceride transfer protein (MTTP) contributed to steatosis, which was reversed by in vivo restoration of Mttp expression. We found that hepatic fibrosis onset can be partially attributed to the action of a miR-122a target, the Klf6 transcript. In addition, Mir122a(-/-) livers exhibited disruptions in a range of pathways, many of which closely resemble the disruptions found in human HCC. Importantly, the reexpression of miR-122a reduced disease manifestation and tumor incidence in Mir122a(-/-) mice. This study demonstrates that mice with a targeted deletion of the Mir122a gene possess several key phenotypes of human liver diseases, which provides a rationale for the development of a unique therapy for the treatment of chronic liver disease and HCC.


Asunto(s)
Neoplasias Hepáticas Experimentales/genética , Neoplasias Hepáticas Experimentales/metabolismo , Hígado/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Animales , Secuencia de Bases , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Hígado Graso/etiología , Hígado Graso/genética , Hígado Graso/metabolismo , Femenino , Perfilación de la Expresión Génica , Genes Supresores de Tumor , Homeostasis , Humanos , Metabolismo de los Lípidos/genética , Lipoproteínas VLDL/metabolismo , Cirrosis Hepática Experimental/etiología , Cirrosis Hepática Experimental/genética , Cirrosis Hepática Experimental/metabolismo , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas Experimentales/etiología , Masculino , Ratones , Ratones Noqueados , Caracteres Sexuales
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