Hepatitis C virus core protein modulates pRb2/p130 expression in human hepatocellular carcinoma cell lines through promoter methylation

Mileo, Anna Maria; Mattarocci, Stefano; Matarrese, Paola; Anticoli, Simona; Abbruzzese, Claudia; Catone, Stefania; Sacco, Rodolfo; Paggi, Marco G.; Ruggieri, Anna

doi:10.1186/s13046-015-0255-1

Cited by 23 publications

(23 citation statements)

References 63 publications

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“…Most primary liver cancers are hepatocellular carcinoma (HCC). The some factors have been reported to contribute to HCC, such as aflatoxin, chronic hepatitis B virus infection, obesity, type 2 diabetes, heavy alcohol consumption, and smoking [ 3 , 4 ]. The treatments for HCC include surgical resection, liver transplantation and ablation, and chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

MiR-130a-3p regulates cell migration and invasion via inhibition of Smad4 in gemcitabine resistant hepatoma cells

Liu

Wang

et al. 2016

J Exp Clin Cancer Res

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BackgroundEmerging evidence demonstrates that microRNAs (miRNAs) play an important role in regulation of cell growth, invasion and metastasis through inhibiting the expression of their targets. It has been reported that miR-130a-3p controls cell growth, migration and invasion in a variety of cancer cells. However, it is unclear whether miR-130a-3p regulates epithelial-mesenchymal transition (EMT) in drug resistant cancer cells. Therefore, in the current study, we explore the role and molecular mechanisms of miR-130a-3p in gemcitabine resistant (GR) hepatocellular carcinoma (HCC) cells.MethodsThe real-time RT-PCR was used to measure the miR-130a-3p expression in GR HCC cells compared with their parental cells. The wound healing assay was conducted to determine the cell migratory activity in GR HCC cells treated with miR-130a-3p mimics. The migration and invasion assays were also performed to explore the role of miR-130a-3p in GR HCC cells. Western blotting analysis was used to measure the expression of Smad4, E-cadherin, Vimentin, and MMP-2 in GR HCC cells after depletion of Smad4. The luciferase assay was conducted to validate whether Smad4 is a target of miR-130a-3p. The student t-test was used to analyze our data.ResultsWe found the down-regulation of miR-130a-3p in GR HCC cells. Moreover, we validate the Smad4 as a potential target of miR-130a-3p. Furthermore, overexpression of miR-130a-3p suppressed Smad4 expression, whereas inhibition of miR-130a-3p increased Smad4 expression. Consistently, overexpression of miR-130a-3p or down-regulation of Smad4 suppressed the cell detachment, attachment, migration, and invasion in GR HCC cells.ConclusionsOur findings provide a molecular insight on understanding drug resistance in HCC cells. Therefore, activation of miR-130a-3p or inactivation of Smad4 could be a novel approach for the treatment of HCC.

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Section: Introductionmentioning

confidence: 99%

MiR-130a-3p regulates cell migration and invasion via inhibition of Smad4 in gemcitabine resistant hepatoma cells

Liu

Wang

et al. 2016

J Exp Clin Cancer Res

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“…Despite no statistically signi cant relationships between pRb immunohistochemistry and prognosis have been observed, our results may suggest that mucinous BOTs, exhibiting low nuclear and high cytoplasmic levels of Rb2/p130, may potentially be considered the BOT histotype with a higher carcinogenic risk. In fact, loss of pRb2/p130 expression has been previously reported to inversely correlate with tumor grade and to be a poor prognostic indicator in several human cancers [14,14,16,18]. Moreover, its cytoplasmic localization, which implicates a loss of function, has been observed in several tumor types, including lymphoma and gastric cancer [29].…”

Section: Discussionmentioning

confidence: 99%

“…Their most important target is the E2F-family of transcription factors which control the expression of genes that mediate G1-S transition [15,16]. The localization of these proteins into the nucleus or around the nuclear membrane has been shown at the molecular level during the different phases of the cell cycle [17,18]. In detail, during the cell progression through the S into the G2/M phases of division cycle, pRB undergoes phosphorylation, while in the late M phase, pRB is rapidly dephosphorylated.…”

Section: Introductionmentioning

confidence: 99%

Role of Retinoblastoma Protein Family (Rb/P105 And Rb2/P130) Expression in the Hystopathological Classification of Borderline Ovarian Tumors

Masciullo

Valdivieso

Amadio

et al. 2020

Preprint

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Background Borderline ovarian tumors (BOT) are uncommon but not rare epithelial ovarian neoplasms, intermediate between benign and malignant categories. Emerging knowledge supports the notion that subtypes of borderline ovarian tumors comprise distinct biologic, pathogenetic, and molecular entities, precluding a single unifying concept for BOT. Therefore, the identification of valuable markers for the diagnosis and classification of these tumors is in need. Among the molecular candidates, the Retinoblastoma (Rb) family members Rb/p105 and Rb2/p130 seem to play a pivotal role in ovarian cancer. In particular, Rb/p105, when in the unphosphorylated form, acts as a growth suppressor and plays a pivotal role in the negative control of the cell cycle and in tumor progression; whereas, the phosphorylated form (p-pRB) activates genic transcription and cellular proliferation. While Rb/p105 is ubiquitously confined to the nuclei of cycling and quiescent cells, Rb2/p130 activity is also regulated by intracellular localization. According to this premise, Rb family members could represent a novel marker in diagnosis and classification risk for patients with borderline ovarian tumors (BOT). Aims In this study, we evaluated the immunohistochemical expression and subcellular localization of proteins of the retinoblastoma (Rb) gene family: Rb/p105 and Rb2/p130 in 65 ovarian borderline tumors (26 serous, 19 sero-mucinous and 20 mucinous subtypes). Results Statistically significant differences were found in nuclear and cytoplasmic expression of Rb/p105 and Rb2/p130 according to different examined histotypes. In detail, the nuclear expression of Rb/p105 and Rb2/p130 was more frequently detected in serous (84.6%) than sero-mucinous (42.1%) and mucinous (50%) types. Conversely, the cytoplasmic expression of Rb2/p130 was not detected in serous tumors and frequently observed in mucinous subtypes (80%). Conclusions Our findings suggest that Rb proteins do not play a key role in the tumor progression of serous borderline tumors since they are always located in the nucleus and no cases showed a cytoplasmic localization. By contrast, the observed higher cytoplasmic expression of Rb2/p130 in mucinous BOTs (intestinal) types, is suggestive of Rb proteins involvement in the cancerogenesis pathway of mucinous ovarian tumors. Our results also suggest that mucinous BOTs of intestinal type, exhibiting low nuclear and high cytoplasmic levels of Rb2/p130 might potentially be considered a high risk category of malignant evolution. Further studies on larger series are needed in order to clarify how BOTs could be stratified in different prognostic groups according to their Rb proteins immunohistochemical profile.

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“…Investigators evaluated the epigenetic role of core protein in whole retinoblastoma (RB) family. They found that core‐induced DNMT1 and DNMT3B overexpression results in silencing two out of three RB family, such as pRb and pRb2/p130 in HuH‐7 core cells . Some of significant TSGs that highlighted to be implicated in HCV‐related HCC include secreted frizzled‐related protein (SFRP1), p16, E‐cadherin, RAR‐β2, etc.…”

Section: Hepatitis Cmentioning

confidence: 99%

DNA methyltransferases in virus‐associated cancers

Charostad

Astani

Goudarzi

et al. 2018

Reviews in Medical Virology

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Summary Human tumor viruses are either casually linked or contribute in the development of human cancers. Viruses can stimulate oncogenesis through affecting diverse biological pathways in human cells. Growing data have demonstrated frequent involvement of one of the most characteristic parts of cellular epigenetic machinery, DNA methylation, in the oncogenesis. DNA methylation of cellular genes is catalyzed by DNA methyltransferases (DNMTs) as a key effector enzyme in this process. Dysregulation of DNMTs can cause aberrant gene methylation in promoter of cancer‐related genes including tumor suppressor genes, resulting in gene silencing. In this regard, the role of tumor viruses is remarkable. Here, in this review, we used published information to elucidate whether tumor viruses are able to manipulate DNMT regulation, and if so, what are its consequences in the process of oncogenesis. This essay also aims to shed light on which cellular pathways have been engaged by viruses to induce DNMTs.

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Hepatitis C virus core protein modulates pRb2/p130 expression in human hepatocellular carcinoma cell lines through promoter methylation

Cited by 23 publications

References 63 publications

MiR-130a-3p regulates cell migration and invasion via inhibition of Smad4 in gemcitabine resistant hepatoma cells

MiR-130a-3p regulates cell migration and invasion via inhibition of Smad4 in gemcitabine resistant hepatoma cells

Role of Retinoblastoma Protein Family (Rb/P105 And Rb2/P130) Expression in the Hystopathological Classification of Borderline Ovarian Tumors

DNA methyltransferases in virus‐associated cancers

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