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1.
Cancer Lett ; 602: 217190, 2024 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-39182558

RESUMEN

DNA- and RNA-binding proteins (DRBPs) are versatile proteins capable of binding to both DNA and RNA molecules. In this study, we identified fibrillarin (FBL) as a key DRBP that is upregulated in liver cancer tissues vs. normal tissues and is correlated with patient prognosis. FBL promotes the proliferation of liver cancer cells both in vitro and in vivo. Mechanistically, FBL interacts with the transcription factor KHSRP, thereby regulating the expression of genes involved in glucose metabolism and leading to the reprogramming of glucose metabolism. Specifically, FBL and KHSRP work together to transcriptionally activate the glycolytic enzyme PFKFB4 by co-occupying enhancer and promoter elements, thereby further promoting liver cancer growth. Collectively, these findings provide compelling evidence highlighting the role of FBL as a transcriptional regulator in liver cancer cells, working in conjunction with KHSRP. The FBL/KHSRP-PFKFB4 regulatory axis holds potential as both a prognostic indicator and a therapeutic target for liver cancer. SIGNIFICANCE: A novel role of FBL in the transcriptional activation of PFKFB4, leading to glucose metabolism reprogramming in liver cancer.

2.
Cancer Lett ; 598: 217088, 2024 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-38945203

RESUMEN

The causal link between long terminal repeat (LTR) retrotransposon-derived lncRNAs and hepatocellular carcinoma (HCC) remains elusive and whether these cancer-exclusive lncRNAs contribute to the effectiveness of current HCC therapies is yet to explore. Here, we investigated the activation of LTR retrotransposon-derived lncRNAs in a broad range of liver diseases. We found that LTR retrotransposon-derived lncRNAs are mainly activated in HCC and is correlated with the proliferation status of HCC. Furthermore, we discovered that an LTR retrotransposon-derived lncRNA, LINC01446, exhibits specific expression in HCC. HCC patients with higher LINC01446 expression had shorter overall survival times. In vitro and in vivo assays showed that LINC01446 promoted HCC growth and angiogenesis. Mechanistically, LINC01446 bound to serine/arginine protein kinase 2 (SRPK2) and activated its downstream target, serine/arginine splicing factor 1 (SRSF1). Furthermore, activation of the SRPK2-SRSF1 axis increased the splicing and expression of VEGF isoform A165 (VEGFA165). Notably, inhibiting LINC01446 expression dramatically impaired tumor growth in vivo and resulted in better therapeutic outcomes when combined with antiangiogenic agents. In addition, we found that the transcription factor MESI2 bound to the cryptic MLT2B3 LTR promoter and drove LINC01446 transcription in HCC cells. Taken together, our findings demonstrate that LTR retrotransposon-derived LINC01446 promotes the progression of HCC by activating the SRPK2/SRSF1/VEGFA165 axis and highlight targeting LINC01446 as a potential therapeutic strategy for HCC patients.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Neovascularización Patológica , Proteínas Serina-Treonina Quinasas , ARN Largo no Codificante , Factores de Empalme Serina-Arginina , Factor A de Crecimiento Endotelial Vascular , Animales , Femenino , Humanos , Masculino , Ratones , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Ratones Endogámicos BALB C , Ratones Desnudos , Neovascularización Patológica/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Retroelementos/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Factores de Empalme Serina-Arginina/genética , Factores de Empalme Serina-Arginina/metabolismo , Transducción de Señal , Secuencias Repetidas Terminales/genética , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo
3.
Biomark Res ; 12(1): 4, 2024 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-38185659

RESUMEN

BACKGROUND: The liver ranks as the sixth most prevalent site of primary cancer in humans, and it frequently experiences metastases from cancers originating in other organs. To facilitate the development of effective treatments and improve survival rates, it is crucial to comprehend the intricate and diverse transcriptome landscape of primary and metastatic liver cancers. METHODS: We conducted long-read isoform sequencing and short-read RNA sequencing using a cohort of 95 patients with primary and secondary liver cancer who underwent hepatic resection. We compared the transcriptome landscapes of primary and metastatic liver cancers and systematically investigated hepatocellular carcinoma (HCC), paired primary tumours and liver metastases, and matched nontumour liver tissues. RESULTS: We elucidated the full-length isoform-level transcriptome of primary and metastatic liver cancers in humans. Our analysis revealed isoform-level diversity in HCC and identified transcriptome variations associated with liver metastatis. Specific RNA transcripts and isoform switching events with clinical implications were profound in liver cancer. Moreover, we defined metastasis-specific transcripts that may serve as predictors of risk of metastasis. Additionally, we observed abnormalities in adjacent paracancerous liver tissues and characterized the immunological and metabolic alterations occurring in the liver. CONCLUSIONS: Our findings underscore the power of full-length transcriptome profiling in providing novel biological insights into the molecular mechanisms underlying tumourigenesis. These insights will further contribute to improving treatment strategies for primary and metastatic liver cancers.

4.
Nucleic Acids Res ; 52(D1): D124-D133, 2024 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-37697439

RESUMEN

Regulatory processes at the RNA transcript level play a crucial role in generating transcriptome diversity and proteome composition in human cells, impacting both physiological and pathological states. This study introduces FLIBase (www.FLIBase.org), a specialized database that focuses on annotating full-length isoforms using long-read sequencing techniques. We collected and integrated long-read (351 samples) and short-read (12 469 samples) RNA sequencing data from diverse normal and cancerous human tissues and cells. The current version of FLIBase comprises a total of 983 789 full-length spliced isoforms, identified through long-read sequences and verified using short-read exon-exon splice junctions. Of these, 188 248 isoforms have been annotated, while 795 541 isoforms remain unannotated. By overcoming the limitations of short-read RNA sequencing methods, FLIBase provides an accurate and comprehensive representation of full-length transcripts. These comprehensive annotations empower researchers to undertake various downstream analyses and investigations. Importantly, FLIBase exhibits a significant advantage in identifying a substantial number of previously unannotated isoforms and tumor-specific RNA transcripts. These tumor-specific RNA transcripts have the potential to serve as a source of immunogenic recurrent neoantigens. This remarkable discovery holds tremendous promise for advancing the development of tailored RNA-based diagnostic and therapeutic strategies for various types of human cancer.


Asunto(s)
Empalme Alternativo , Bases de Datos Genéticas , Neoplasias , Humanos , Neoplasias/genética , Isoformas de Proteínas/genética , ARN , Análisis de Secuencia de ARN/métodos , Transcriptoma
5.
Adv Sci (Weinh) ; 10(26): e2302425, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37431681

RESUMEN

Aldolase A (ALDOA), a crucial glycolytic enzyme, is often aberrantly expressed in various types of cancer. Although ALDOA has been reported to play additional roles beyond its conventional enzymatic role, its nonmetabolic function and underlying mechanism in cancer progression remain elusive. Here, it is shown that ALDOA promotes liver cancer growth and metastasis by accelerating mRNA translation independent of its catalytic activity. Mechanistically, ALDOA interacted with insulin- like growth factor 2 mRNA-binding protein 1 (IGF2BP1) to facilitate its binding to m6 A-modified eIF4G mRNA, thereby increasing eIF4G protein levels and subsequently enhancing overall protein biosynthesis in cells. Importantly, administration of GalNAc-conjugated siRNA targeting ALDOA effectively slows the tumor growth of orthotopic xenografts. Collectively, these findings uncover a previously unappreciated nonmetabolic function of ALDOA in modulating mRNA translation and highlight the potential of specifically targeting ALDOA as a prospective therapeutic strategy in liver cancer.


Asunto(s)
Fructosa-Bifosfato Aldolasa , Neoplasias Hepáticas , Humanos , Fructosa-Bifosfato Aldolasa/genética , Factor 4G Eucariótico de Iniciación , Línea Celular Tumoral , Neoplasias Hepáticas/genética , ARN Interferente Pequeño/metabolismo
6.
Mol Metab ; 75: 101766, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37406987

RESUMEN

Sufficient evidence has linked many different types of cancers and T2D through shared risk factors; however, the underlying mechanisms are not fully understood. α-Hydroxybutyrate (α-HB), a byproduct metabolite increased in diabetes and cancer, including colorectal cancer (CRC), triggers lactate dehydrogenase A (LDHA) nuclear translocation. Nuclear LDHA markedly extends NF-κB nuclear retention by interacting with phosphorylated p65, leading to an increase in TNF-α production, impaired insulin secretion and the exacerbation of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CRC and high-fat diet (HFD)-induced type 2 diabetes. Furthermore, metformin interrupted this process by inhibiting the transcription of FOXM1 and c-MYC, the resultant downregulation of LDHA expression and α-HB-induced LDHA nuclear translocation. Thus, the results reveal the elevated α-HB level could be a novel shared risk factor of linking CRC, diabetes and the use of metformin treatment, as well as highlight the importance of preventing NF-κB activation for protecting against cancer and diabetes.


Asunto(s)
Neoplasias Colorrectales , Diabetes Mellitus Tipo 2 , Humanos , FN-kappa B/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Neoplasias Colorrectales/metabolismo , Transducción de Señal
7.
Cell Death Dis ; 14(6): 351, 2023 06 08.
Artículo en Inglés | MEDLINE | ID: mdl-37291119

RESUMEN

In addition to the classical role as a serum effector system of innate immunity, accumulating evidence suggests that intracellular complement components have indispensable functions in immune defense, T cell homeostasis, and tumor cell proliferation and metastasis. Here, we revealed that complement component 3 (C3) is remarkably upregulated in paclitaxel (PTX)-resistant non-small cell lung cancer (NSCLC) cells and that knockdown of C3 promoted PTX-induced cell apoptosis, sensitizing resistant cells to PTX therapy. Ectopic C3 decreased PTX-induced apoptosis and induced resistance to PTX treatment in original NSCLC cells. Interestingly, C3b, the activated fragment of C3, was found to translocate into the nucleus and physically associate with the HDAC1/2-containing SIN3A complex to repress the expression of GADD45A, which plays an important role in cell growth inhibition and apoptosis induction. Importantly, C3 downregulated GADD45A by enhancing the binding of the SIN3A complex with the promoter of GADD45A, thus decreasing the H3Ac level to compress chromatin around the GADD45A locus. Subsequently, ectopic GADD45A promoted PTX-induced cell apoptosis, sensitizing resistant cells to PTX therapy, and insufficiency of GADD45A in original cancer cells induced resistance to PTX treatment. These findings identify a previously unknown nucleus location and oncogenic property for C3 in chemotherapy and provide a potential therapeutic opportunity to overcome PTX resistance.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Paclitaxel , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Complemento C3b , Resistencia a Antineoplásicos , Proliferación Celular , Apoptosis , Línea Celular Tumoral , Histona Desacetilasa 1/genética
8.
Nat Commun ; 13(1): 6803, 2022 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-36357395

RESUMEN

Transcribed RNAs undergo various regulation and modification to become functional transcripts. Notably, cancer transcriptome has not been fully characterized at transcript resolution. Herein, we carry out a reference-based transcript assembly across >1000 cancer cell lines. We identify 498,255 transcripts, approximately half of which are unannotated. Unannotated transcripts are closely associated with cancer-related hallmarks and show clinical significance. We build a high-confidence RNA binding protein (RBP)-transcript regulatory network, wherein most RBPs tend to regulate transcripts involved in cell proliferation. We identify numerous transcripts that are highly associated with anti-cancer drug sensitivity. Furthermore, we establish RBP-transcript-drug axes, wherein PTBP1 is experimentally validated to affect the sensitivity to decitabine by regulating KIAA1522-a6 transcript. Finally, we establish a user-friendly data portal to serve as a valuable resource for understanding cancer transcriptome diversity and its potential clinical utility at transcript level. Our study substantially extends cancer RNA repository and will facilitate anti-cancer drug discovery.


Asunto(s)
Neoplasias , Transcriptoma , Transcriptoma/genética , ARN/metabolismo , Proteínas de Unión al ARN/metabolismo , Análisis de Secuencia de ARN , Neoplasias/tratamiento farmacológico , Neoplasias/genética
9.
Cell Death Dis ; 13(8): 732, 2022 08 25.
Artículo en Inglés | MEDLINE | ID: mdl-36008383

RESUMEN

Liver cancer stemness refers to the stem cell-like phenotype of hepatocarcinoma cells and is closely related to a high degree of tumour malignancy. Here, we identified AT-rich interacting domain 3A (ARID3A) as one of the most upregulated stemness-related transcription factors in liver cancer by an in vitro functional screen. ARID3A can promote liver cancer cell viability and metastasis both in vitro and in vivo. Mechanistically, ARID3A interacts with CEP131 and transcriptionally activates KDM3A by co-occupying its promoter element, further upregulating the expression of downstream embryonic stem (ES) signature genes via demethylation of H3K9me2. ARID3A and CEP131 promote an ES cell gene signature through activation of KDM3A and contribute to the poor prognosis of liver cancer patients. Collectively, these results provide evidence highlighting a transcription-dependent mechanism of ARID3A in stemness regulation in liver cancer. The ARID3A/CEP131-KDM3A regulatory circuit could serve as a prognostic indicator and potential therapeutic target for liver cancer.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Proteínas del Citoesqueleto/metabolismo , Proteínas de Unión al ADN , Neoplasias Hepáticas , Factores de Transcripción/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Células Madre Embrionarias/metabolismo , Humanos , Histona Demetilasas con Dominio de Jumonji/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Regiones Promotoras Genéticas/genética
10.
Cancer Lett ; 538: 215711, 2022 07 10.
Artículo en Inglés | MEDLINE | ID: mdl-35490918

RESUMEN

Alternative splicing is an important RNA processing event that contributes to RNA complexity and protein diversity in cancer. Accumulating evidence demonstrates the essential roles of some alternatively spliced genes in carcinogenesis. However, the potential roles of alternatively spliced genes in hepatocellular carcinoma (HCC) are still largely unknown. Here we showed that the HnRNP Associated with Lethal Yellow Protein Homolog (RALY) gene is upregulated and associated with poor outcomes in HCC patients. RALY acts as a tumor-promoting factor by cooperating with splicing factor 3b subunit 3 (SF3B3) and modulating the splicing switch of Metastasis Associated 1 (MTA1) from MTA-S to MTA1-L. Normally, MTA1-S inhibits cell proliferation by reducing the transcription of cholesterol synthesis genes. In HCC, RALY and SF3B3 cooperate to regulate the MTA1 splicing switch, leading to a reduction in the MTA1-S level, and alleviating the inhibitory effect of MTA1-S on cholesterol synthesis genes, thus promoting HCC cell proliferation. In conclusion, our results revealed that the RALY-SF3B3/MTA1/cholesterol synthesis pathway contributes essentially to hepatic carcinogenesis and could serve as a promising therapeutic target for HCC.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Empalme Alternativo , Carcinogénesis/genética , Carcinoma Hepatocelular/patología , Colesterol/biosíntesis , Regulación Neoplásica de la Expresión Génica , Ribonucleoproteína Heterogénea-Nuclear Grupo C/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo C/metabolismo , Humanos , Neoplasias Hepáticas/patología , Proteínas de Unión al ARN/genética , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Transactivadores/genética , Transactivadores/metabolismo
11.
Adv Sci (Weinh) ; 9(21): e2105126, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35603967

RESUMEN

Metabolic reprogramming is often observed in carcinogenesis, but little is known about the aberrant metabolic genes involved in the tumorigenicity and maintenance of stemness in cancer cells. Sixty-seven oncogenic metabolism-related genes in liver cancer by in vivo CRISPR/Cas9 screening are identified. Among them, acetyl-CoA carboxylase 1 (ACC1), aldolase fructose-bisphosphate A (ALDOA), fatty acid binding protein 5 (FABP5), and hexokinase 2 (HK2) are strongly associated with stem cell properties. HK2 further facilitates the maintenance and self-renewal of liver cancer stem cells. Moreover, HK2 enhances the accumulation of acetyl-CoA and epigenetically activates the transcription of acyl-CoA synthetase long-chain family member 4 (ACSL4), leading to an increase in fatty acid ß-oxidation activity. Blocking HK2 or ACSL4 effectively inhibits liver cancer growth, and GalNac-siHK2 administration specifically targets the growth of orthotopic tumor xenografts. These results suggest a promising therapeutic strategy for the treatment of liver cancer.


Asunto(s)
Coenzima A Ligasas , Hexoquinasa , Neoplasias Hepáticas , Células Madre Neoplásicas , Sistemas CRISPR-Cas/genética , Coenzima A Ligasas/genética , Coenzima A Ligasas/metabolismo , Proteínas de Unión a Ácidos Grasos/genética , Proteínas de Unión a Ácidos Grasos/metabolismo , Ácidos Grasos/metabolismo , Hexoquinasa/genética , Hexoquinasa/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Células Madre Neoplásicas/metabolismo
12.
Biomark Res ; 10(1): 27, 2022 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-35473935

RESUMEN

The production of functional mature RNA transcripts from genes undergoes various pre-transcriptional regulation and post-transcriptional modifications. Accumulating studies demonstrated that gene transcription carries out in tissue and cancer type-dependent ways. However, RNA transcript-level specificity analysis in large-scale transcriptomics data across different normal tissue and cancer types is lacking. We applied reference-based de novo transcript assembly and quantification of 27,741 samples across 33 cancer types, 29 tissue types, and 25 cancer cell line types. We totally identified 231,836 specific RNA transcripts (SRTs) across various tissue and cancer types, most of which are found independent of specific genes. Almost half of tumor SRTs are also tissue-specific but in different tissues. Furthermore, we found that 10 ~ 20% of tumor SRTs in most tumor types were testis-specific. The SRT database (SRTdb) was constructed based on these resources. Taking liver cancer as an example, we showed how SRTdb resource is utilized to optimize the identification of RNA transcripts for more precision diagnosis of particular cancers. Our results provide a useful resource for exploring transcript specificity across various cancer and tissue types, and boost the precision medicine for tumor patients.

13.
Comput Biol Med ; 144: 105376, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35286894

RESUMEN

Hepatocellular carcinoma (HCC) is a highly lethal and heterogeneous disease with a poor prognosis and no effective treatments. Herein, we presented a pathway-guided computational framework to establish a metabolic signature with the capacity for HCC prognosis prediction. By using the TCGA dataset as a training cohort (n = 365), we built an eight-gene (ACADS, ALDH1A2, FTCD, GOT2, GPX7, HADHA, LDHA and UGT2A1) risk score called the MGP score from the 20 metabolic pathways downregulated in HCC. The robustness of the MGP model was successfully validated in seven other independent cohorts (LIRI-JP, n = 231; Chinese, n = 159; GSE148355, n = 33; GSE14520, n = 225; GSE54236, n = 81; E-TABM-36, n = 41; and qPCR, n = 126). Moreover, three subtypes, L, H1 and H2, with distinct clinical outcomes were further stratified by using 761 HCC patients in the combined RNA-Seq cohort. Further analysis identified strong negative associations between metabolic pathways and other molecular features, including immune infiltration, expression of immune checkpoint genes, and hypoxic conditions, among the three subtypes. In 81 liver cancer cell lines, the MGP score indicated sensitivity to three preclinical agents (erastin, piperlongumine and PI-103), which may have potential therapeutic implications for the high-MGP score subtypes H1 and H2. Overall, our analysis highlights the potential of applying the MGP score for prognosis prediction and precision therapy for HCC.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Perfilación de la Expresión Génica , Glucuronosiltransferasa , Humanos , Hipoxia , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética
14.
Cancer Res ; 82(10): 1937-1952, 2022 05 16.
Artículo en Inglés | MEDLINE | ID: mdl-35290436

RESUMEN

RNA helicases are dysregulated in tumors. Here, we identified DHX37 as one of the top RNA helicase genes with upregulated expression in hepatocellular carcinoma (HCC). DHX37 promoted proliferation of liver cancer cells in vitro and in vivo. Epigenomic profiling of DHX37-knockdown and control HCC cells revealed that DHX37 is associated with superenhancer activity. Mechanistically, DHX37 interacted with pleiotropic regulator 1 (PLRG1) to transcriptionally activate cyclin D1 (CCND1) expression via co-occupation of its promoter and superenhancer elements. DHX37 and PLRG1 promoted liver cancer cell proliferation and contributed to the poor prognosis of patients with HCC. Importantly, CCND1 inhibitors were effective as antiproliferative agents for liver cancer. These results together demonstrate a cooperative mechanistic interaction between DHX37 and PLRG1 that regulates CCND1 expression and promotes liver cancer progression, advancing our understanding of the epigenetic and transcriptional dysregulations mediated by RNA helicases and superenhancers in HCC. SIGNIFICANCE: This work characterizes a novel mechanism of superenhancer-driven cyclin D1 upregulation by DHX37 and PLRG1, implicating this pathway as a potential therapeutic target in hepatocellular carcinoma.


Asunto(s)
Carcinoma Hepatocelular , Ciclina D1 , Péptidos y Proteínas de Señalización Intracelular , Neoplasias Hepáticas , Proteínas Nucleares , ARN Helicasas , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular/genética , Ciclina D1/genética , Ciclina D1/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Hepáticas/patología , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , ARN Helicasas/genética , ARN Helicasas/metabolismo
15.
Cell Discov ; 7(1): 118, 2021 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-34903728

RESUMEN

PTEN is a crucial tumor suppressor and loss of PTEN protein is involved in various cancers. However, the detailed molecular mechanisms of PTEN loss in cancers remain elusive, especially the involvement of lncRNAs. Here, lncRNA RP11-295G20.2 is found to be significantly upregulated in hepatocellular carcinoma (HCC) and promotes the growth of liver cancer cells both in vitro and in vivo. Furthermore, RP11-295G20.2 inhibits autophagy in liver cancer cells. Interestingly, RP11-295G20.2 directly binds to the PTEN protein and leads to its degradation. RP11-295G20.2 expression is inversely correlated with PTEN protein expression in 82 TCGA/TCPA-LIHC samples. Surprisingly, RP11-295G20.2-induced PTEN degradation occurs through the lysosomal pathway instead of the proteasome pathway. RP11-295G20.2 binds to the N terminus of PTEN and facilitates the interaction of p62 with PTEN. Thus, PTEN is translocated into lysosomes and degraded. RP11-295G20.2 also influences AKT phosphorylation and forkhead box O 3a (FOXO3a) translocation into the nucleus, in turn regulating the transcription of autophagy-related genes. Collectively, RP11-295G20.2 directly binds to PTEN and enables its lysosomal degradation. This newly identified RP11-295G20.2/PTEN axis reveals an unexplored molecular mechanism regarding PTEN loss in liver cancer and might provide new therapeutic benefits for liver cancer patients.

16.
Adv Sci (Weinh) ; 8(13): 2001701, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34258149

RESUMEN

Circular RNAs (circRNAs) are an intriguing class of widely prevalent endogenous RNAs, the vast majority of which have not been characterized functionally. Here, we identified a novel oncogenic circRNA originating from the back-splicing of Exon2 and Exon3 of a tumor suppressor gene, ARHGAP35 (also known as P190-A), termed as circARHGAP35. have observe that circARHGAP35 and linear ARHGAP35 have antithetical expression and functions. Interestingly, circARHGAP35 contains a 3867 nt long ORF with an m6A-modified start codon and encodes a truncated protein comprising four FF domains and lacking the Rho GAP domain. Mechanistically, circARHGAP35 protein promotes cancer cell progression by interacting with TFII-I protein in the nucleus. The RNA binding protein, HNRNPL, facilitates the formation of circARHGAP35. Clinically, circARHGAP35 is associated with poor survival in cancer patients. Our findings characterize an oncogenic circRNA and demonstrate a novel mechanism of oncogene activation in cancer by circRNA through the production of a truncated protein.


Asunto(s)
Proteínas Activadoras de GTPasa/genética , Proteínas Activadoras de GTPasa/metabolismo , Ribonucleoproteínas Nucleares Heterogéneas/genética , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Neoplasias/genética , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Animales , Modelos Animales de Enfermedad , Masculino , Ratones , Neoplasias/metabolismo
17.
Proc Natl Acad Sci U S A ; 118(29)2021 07 20.
Artículo en Inglés | MEDLINE | ID: mdl-34266953

RESUMEN

p53 inactivation is highly associated with tumorigenesis and drug resistance. Here, we identify a long noncoding RNA, the RNA component of mitochondrial RNA-processing endoribonuclease (RMRP), as an inhibitor of p53. RMRP is overexpressed and associated with an unfavorable prognosis in colorectal cancer. Ectopic RMRP suppresses p53 activity by promoting MDM2-induced p53 ubiquitination and degradation, while depletion of RMRP activates the p53 pathway. RMRP also promotes colorectal cancer growth and proliferation in a p53-dependent fashion in vitro and in vivo. This anti-p53 action of RMRP is executed through an identified partner protein, SNRPA1. RMRP can interact with SNRPA1 and sequester it in the nucleus, consequently blocking its lysosomal proteolysis via chaperone-mediated autophagy. The nuclear SNRPA1 then interacts with p53 and enhances MDM2-induced proteasomal degradation of p53. Remarkably, ablation of SNRPA1 completely abrogates RMRP regulation of p53 and tumor cell growth, indicating that SNRPA1 is indispensable for the anti-p53 function of RMRP. Interestingly and significantly, poly (ADP-ribose) polymerase (PARP) inhibitors induce RMRP expression through the transcription factor C/EBPß, and RMRP confers tumor resistance to PARP inhibition by preventing p53 activation. Altogether, our study demonstrates that RMRP plays an oncogenic role by inactivating p53 via SNRPA1 in colorectal cancer.


Asunto(s)
ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Proteína p53 Supresora de Tumor/genética , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , Humanos , Unión Proteica , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Ribonucleoproteína Nuclear Pequeña U2/genética , Ribonucleoproteína Nuclear Pequeña U2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo
18.
Oncogene ; 40(29): 4770-4782, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34148056

RESUMEN

Numerous studies suggest an important role for copy number alterations (CNAs) in cancer progression. However, CNAs of long intergenic noncoding RNAs (lincRNAs) in ovarian cancer (OC) and their potential functions have not been fully investigated. Here, based on analysis of The Cancer Genome Atlas (TCGA) database, we identified in this study an oncogenic lincRNA termed LINC00662 that exhibited a significant correlation between its CNA and its increased expression. LINC00662 overexpression is highly associated with malignant features in OC patients and is a prognostic indicator. LINC00662 significantly promotes OC cell proliferation and metastasis in vitro and in vivo. Mechanistically, LINC00662 is stabilized by heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1). Moreover, LINC00662 exerts oncogenic effects by interacting with glucose-regulated protein 78 (GRP78) and preventing its ubiquitination in OC cells, leading to activation of the oncogenic p38 MAPK signaling pathway. Taken together, our results define an oncogenic role for LINC00662 in OC progression mediated via GRP78/p38 signaling, with potential implications regarding therapeutic targets for OC.


Asunto(s)
Carcinoma Epitelial de Ovario , Proliferación Celular , Femenino , Humanos , Oncogenes , Pronóstico , ARN Largo no Codificante
19.
STAR Protoc ; 2(1): 100353, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33665633

RESUMEN

Animal models of liver cancer are instrumental in the study of hepatocarcinogenesis and development of novel therapeutic approaches. Here, we describe steps to establish liver cancer in a rat model, via chronic administration of diethylnitrosamine. This causes liver tumors with a sequential progression of hepatitis, cirrhosis, and tumor formation, which closely mimics the development of human liver cancer. This protocol was optimized to significantly increase the incidence of liver tumor formation and reduce the duration of the procedure. For complete details on the use and execution of this protocol, please refer to Chen et al. (2020).


Asunto(s)
Carcinogénesis , Dietilnitrosamina/toxicidad , Cirrosis Hepática Experimental , Neoplasias Hepáticas Experimentales , Animales , Carcinogénesis/inducido químicamente , Carcinogénesis/metabolismo , Carcinogénesis/patología , Humanos , Inflamación/inducido químicamente , Inflamación/metabolismo , Inflamación/patología , Cirrosis Hepática Experimental/inducido químicamente , Cirrosis Hepática Experimental/metabolismo , Cirrosis Hepática Experimental/patología , Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas Experimentales/patología , Masculino , Ratas , Ratas Sprague-Dawley
20.
Med Rev (Berl) ; 1(2): 150-171, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37724303

RESUMEN

In the past several years, nanopore sequencing technology from Oxford Nanopore Technologies (ONT) and single-molecule real-time (SMRT) sequencing technology from Pacific BioSciences (PacBio) have become available to researchers and are currently being tested for cancer research. These methods offer many advantages over most widely used high-throughput short-read sequencing approaches and allow the comprehensive analysis of transcriptomes by identifying full-length splice isoforms and several other posttranscriptional events. In addition, these platforms enable structural variation characterization at a previously unparalleled resolution and direct detection of epigenetic marks in native DNA and RNA. Here, we present a comprehensive summary of important applications of these technologies in cancer research, including the identification of complex structure variants, alternatively spliced isoforms, fusion transcript events, and exogenous RNA. Furthermore, we discuss the impact of the newly developed nanopore direct RNA sequencing (RNA-Seq) approach in advancing epitranscriptome research in cancer. Although the unique challenges still present for these new single-molecule long-read methods, they will unravel many aspects of cancer genome complexity in unprecedented ways and present an encouraging outlook for continued application in an increasing number of different cancer research settings.

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