Loss of Runt-related transcription factor 3 induces resistance to 5-fluorouracil and cisplatin in hepatocellular carcinoma

Kataoka, Junro; Shiraha, Hidenori; Horiguchi, Shigeru; Sawahara, Hiroaki; Uchida, Daisuke; Nagahara, Teruya; Iwamuro, Masaya; Morimoto, Hiroki; Takeuchi, Yasuto; Kuwaki, Kenji; Onishi, Hideki; Nakamura, Shinichiro; Takaki, Akinobu; Nouso, Kazuhiro; Yagi, T.; Yamamoto, Kazuhide; Okada, Hiroyuki

doi:10.3892/or.2016.4681

Cited by 14 publications

(13 citation statements)

References 35 publications

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“…Patients with HCC initially respond to cisplatin therapy but resistance frequently occurs, which is associated with increased DNA repair, altered cell accumulation and increased drug efflux mediated by multidrug resistance proteins (20). It has been reported that cisplatin resistance in HCC may occur through the loss of Runt-associated transcription factor 3 and upregulation of cyclophilin B (21,22). Recently, certain key biomarkers of cisplatin resistance have revealed novel molecular mechanisms of resistance (23).…”

Section: Discussionmentioning

confidence: 99%

Cisplatin resistance‑associated circRNA_101237 serves as a prognostic biomarker in hepatocellular carcinoma

et al. 2020

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Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated mortality worldwide. Despite clinical advances, the survival rate of patients with HCC remains low, as most patients are diagnosed with HCC when they are already at the advanced stage. Certain circular RNAs (circRNAs) are closely associated with the development of liver cancer. In the present study, a circRNA array was performed to screen differentially expressed circRNAs in HCC tissues. The further analysis focused on the newly identified circRNA_101237, the host gene of which, cyclin-dependent kinase 8, is located at chr13:26974589-26975761. CircRNA_101237 was determined to be upregulated in tumor tissue and serum of patients with HCC as compared with that in paracancerous tissues and the serum of healthy controls, respectively. In addition, the expression of circRNA_101237 was associated with tumor size, lymph node metastasis, distant metastasis and TNM stage. Univariate and multivariate analysis indicated that serum circRNA_101237 levels were an independent predictor of survival prognosis in patients with HCC. The overall survival of patients with high expression of circRNA_101237 was reduced compared with that of patients with low expression of circRNA_101237. Of note, cisplatin induced the expression of circRNA_101237 in HCC cells in a dose-and time-dependent manner in vitro, and the levels of circRNA_101237 in the serum of patients with cisplatin-resistant HCC and in cisplatin-resistant Huh7 cells were increased. The present study provided novel insight into the use of circRNA_101237 as a diagnostic biomarker for HCC and a potential therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Cisplatin resistance‑associated circRNA_101237 serves as a prognostic biomarker in hepatocellular carcinoma

et al. 2020

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“…For this reason, genes with this structure are highly susceptible to be regulated by methylation. 4,5 DNA methylation is an epigenetic modification that regulates the gene expression and provides a mechanism for conveying and preserving epigenetic information through DNA replication and cell division. Accumulating studies have indicated that aberrant changes in DNA methylation are amongst the most common molecular alterations associated with tumorigenesis and hypermethylation of the promoter region of various cancer suppressor genes is recognized as one of the most frequent mechanisms for loss of gene function.…”

Section: Introductionmentioning

confidence: 99%

<p>Regulation of <em>RUNX3</em> Expression by DNA Methylation in Prostate Cancer</p>

Yang¹,

Wang²,

Reheman³

2020

CMAR

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To investigate the role of DNA methylation in the regulation of Runt-related transcription factor 3 (RUNX3) and the effect of such mechanism on the proliferation of prostate cancer (PCa) cells. Materials and Methods: The methylation of the RUNX3 in the promoter region in PCa cells was detected by bisulfite-sequencing PCR (BSP). Following treatment of the PCa cells with DNA methylation transferase inhibitor 5-AZA-2ʹ-deoxycytidine (AZA), the effect on methylation level and expression of RUNX3 were analyzed by qRT-PCR, Western blot, and BSP assays. Furthermore, we investigated the effect of the demethylated RUNX3 on proliferation, cell cycle and apoptosis of PCa cells using CCK-8 and flow cytometry assays. Using the DNA methylation transferase (DNMT3b) knockout or overexpression models, the relationship between DNMT3b and RUNX3 methylation was further assessed by qRT-PCR, Western blot and methylation-specific PCR (MSP). Results: The results indicated that the methylation level of RUNX3 in PCa cell lines was significantly higher than that of normal prostate epithelial (RWPE-1) cells. Furthermore, treatment with AZA not only promoted the demethylation of RUNX3 but also restored the mRNA and protein expression of RUNX3, and the reactivation of expression of the later exhibited its anti-tumor effects through regulation of the cycle progression in PCa cells. Moreover, DNMT3b could regulate the expression level of RUNX3 by altering the DNA methylation of the RUNX3 in PCa cells. Conclusion: RUNX3 is hypermethylated in a panel of PCa cell lines; inhibition of DNA methylation of RUNX3 could restore its gene expression, which could promote its anticancer effect. Thus, RUNX3 may serve as a novel putative molecular target gene for PCa therapy.

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“…We identified the most likely targets of miR‐335‐5p as CDC42, CDK2, CSNK1G2, EIF2C2, EIF5, LIMK1, NRG1, PLK2, RGS19, TCF3, THBS1, YBX1, and ZMYND8. Among these genes, CDC 42, CDK2, EIF2C2, EIF5, LIMK1, NRG1, PLK2, RGS19, TCF3, THBS1, as well as YBX1 have been implicated in hepatocellular carcinoma, and some of them are related to invasion and metastasis. Out of these 13 downstream miR‐335‐5p targets, CSNK1G2 and ZMYND8 are reported here for the first time as playing a role in HCC.…”

Section: Discussionmentioning

confidence: 99%

“…We identified the most likely targets of miR-335-5p as CDC42 (Cell division control protein 42 homolog), CDK2 (Cyclin-dependent kinase 2), CSNK1G2 (Casein kinase 1 gamma 2), EIF2C2 (Protein argonaute-2), EIF5 (Eukaryotic translation initiation factor-5), LIMK1 (LIM Domain Kinase 1), NRG1 (Neuregulin 1), PLK2 (Polo Like Kinase 2), RGS19 (G-protein signaling 19), TCF3 (Transcription Factor 3), THBS1 (Thrombospondin 1), YBX1 (Y-Box Binding Protein 1) and ZMYND8 (human Zinc Finger MYND-type containing 8). Among these genes, CDC 42(19, 20), CDK2(21, 22), EIF2C2(23, 24), EIF5(25, 26), LIMK1(27), NRG1(28), PLK2(29), RGS19(30), TCF3(31), THBS1(32) as well as YBX1(33) have been implicated in hepatocellular carcinoma, and some of them are related to invasion and metastasis. Out of these 13 downstream miR-335-5p targets, CSNK1G2 and ZMYND8 are reported here for the first time as playing a role in HCC.…”

Section: Discussionmentioning

confidence: 99%

Exosome miR‐335 as a novel therapeutic strategy in hepatocellular carcinoma

et al. 2018

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Hepatocellular carcinoma (HCC) is a common and deadly cancer. Most cases of HCC arise in a cirrhotic/fibrotic liver, indicating that environment may play a paramount role in cancer genesis. Previous studies from our group and others have shown that, in desmoplastic cancers, there is a rich intercellular communication between activated, cancer-associated fibroblasts and cancer cells. Moreover, extracellular vesicles (EVs), or exosomes, have been identified as an important arm of this intercellular communication platform. Finally, these studies have shown that EVs can carry microRNA (miR) species in vivo and deliver them to desmoplastic cancers. The precise role played by activated liver fibroblasts/stellate cells in HCC development is insufficiently known. Based on previous studies, it appears plausible that activated fibroblasts produce signals carried by EVs that promote HCC genesis. In the current study, we first hypothesized and then demonstrated that stellate cell-derived EVs 1) can be loaded with an miR species of choice (miR-335-5p); 2) are taken up by HCC cells in vitro and more importantly in vivo; 3) can supply the miR-335-5p cargo to recipient HCC cells in vitro as well as in vivo; and 4) inhibit HCC cell proliferation and invasion in vitro as well as induce HCC tumor shrinkage in vivo. Finally, we identified messenger RNA targets for miR-335 that are down-regulated after treatment with EV-miR-335-5p. This study informs potential therapeutic strategies in HCC, whereby stellate cell-derived EVs are loaded with therapeutic nucleic acids and delivered in vivo. (Hepatology 2018;67:940-954).

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Loss of Runt-related transcription factor 3 induces resistance to 5-fluorouracil and cisplatin in hepatocellular carcinoma

Cited by 14 publications

References 35 publications

Cisplatin resistance‑associated circRNA_101237 serves as a prognostic biomarker in hepatocellular carcinoma

Cisplatin resistance‑associated circRNA_101237 serves as a prognostic biomarker in hepatocellular carcinoma

<p>Regulation of <em>RUNX3</em> Expression by DNA Methylation in Prostate Cancer</p>

Exosome miR‐335 as a novel therapeutic strategy in hepatocellular carcinoma

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