Downregulation of the micro<scp>RNA</scp> biogenesis components and its association with poor prognosis in hepatocellular carcinoma

Kitagawa, Noriyuki; Ojima, Hidenori; Shirakihara, Takuya; Shimizu, Hiroko; Kokubu, Akiko; Urushidate, Tomoko; Totoki, Yasushi; Kosuge, Tomoo; Miyagawa, Shinichi; Shibata, Tatsuhiro

doi:10.1111/cas.12126

Cited by 73 publications

(58 citation statements)

References 35 publications

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“…5, mRNA levels of DGCR8 and Dicer1 were significantly reduced in high-dose group compared with control group. These results are consistent with previous reports on liver carcinogenesis and regeneration studies 24,25 . Also, our proteomic data showed that some of the differentially expressed proteins were closely related with liver regeneration as well (data not shown).…”

Section: Resultssupporting

confidence: 94%

Ochratoxin A induced early hepatotoxicity: new mechanistic insights from microRNA, mRNA and proteomic profiling studies

Yang

Chen

et al. 2014

Sci Rep

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The mycotoxin ochratoxin A (OTA) is found widely in agricultural commodities. OTA can induce various toxicities. In this study, rats were gavaged with OTA for different weeks. Then, the expression of microRNAs, mRNAs and proteins were measured in the rat livers treated with OTA for 13 weeks. Our sequencing data suggests that the medial and the high doses of OTA exert different effects on livers. Five distinctive pathways were induced after OTA treatment as collectively demonstrated at miRNA, mRNA and protein levels. Two (primary bile acid biosynthesis, and metabolism of xenobiotics by cytochrome P450) are directly associated with liver damage, whereas the remaining pathways (arginine and proline metabolism, cysteine and methionine metabolism, and PPAR signaling pathway) cause metabolic disease. This study reveals OTA-induced early hepatotoxicity for the first time by combining multi-omics methods. The novel metabolic pathways may contribute to the pathogenesis of metabolic diseases later in life.O chratoxin A (OTA) is a low molecular weight mycotoxin produced by certain strains of filamentous fungi of the Aspergillus and Penicillium genera and has been detected in a large variety of agricultural commodities. OTA carries potential health-associated risks and has been classified as a possible human carcinogen (group 2B) by the International Agency for Research on Cancer 1 . OTA has previously been found to induce various toxic effects including nephrotoxicity, hepatotoxicity, immunotoxicity, genotoxicity, carcinogenicity, teratogenicity, neurotoxicity and mutagenicity.The liver is one of the major target organs of OTA biotransformation. Although, some early hepatotoxicity studies employed relative high concentrations of OTA and found remarkable liver lesion 2,3 , lower doses of OTA did not provoke significant pathological changes 4-6 . Most of the previous studies have been extensively focused on OTA-induced kidney damage, less on liver. However, it is still unknown how OTA affects the liver which is the largest detoxification organ of body. Therefore, the identification of early hepatotoxicity can be helpful to understand the mechanism of some diseases that may be developed and progressed by OTA in later stage, and to prevent these diseases in early stage to improve human health.Omics approaches, such as transcriptome and proteome, are promising to detect the pathological changes of liver at a molecular level. Till date, omics technology has been employed only in a few studies to understand the mechanism of OTA hepatotoxicity. Moreover, a high-throughput microarray profiling study on HepG2 liver cell transcriptome demonstrated that multiple hepatic metabolism genes are modulated by OTA exposure 7 . In addition, proteomic approaches have helped identify key proteins in the livers of pigs treated with OTA 8 . These omics approaches have widened our view about OTA hepatotoxicity, however the mechanism of OTA actions remains largely unknown.Recently, microRNAs (miRNAs) in animals and plants are shown to play an impor...

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Section: Resultssupporting

confidence: 94%

Ochratoxin A induced early hepatotoxicity: new mechanistic insights from microRNA, mRNA and proteomic profiling studies

Yang

Chen

et al. 2014

Sci Rep

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“…Downregulation of TARBP2 stabilized Nanog protein expression and enhanced sorafenib resistance in HCC cells. Among the components of miRNA biogenesis, downregulation of DGCR8, Dicer, p68, and p72 has been associated with a poor prognosis in HCC (Kitagawa et al ., ). Our results demonstrated that suppression of TARBP2 expression promoted sorafenib resistance in HCC cells (Fig.…”

Section: Discussionmentioning

confidence: 97%

TARBP2‐mediated destabilization of Nanog overcomes sorafenib resistance in hepatocellular carcinoma

Lai

Hong

et al. 2019

Molecular Oncology

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Hepatocellular carcinoma ( HCC ) is a lethal human malignancy and a leading cause of cancer‐related death worldwide. Patients with HCC are often diagnosed at an advanced stage, and the prognosis is usually poor. The multikinase inhibitor sorafenib is the first‐line treatment for patients with advanced HCC . However, cases of primary or acquired resistance to sorafenib have gradually increased, leading to a predicament in HCC therapy. Thus, it is critical to investigate the mechanism underlying sorafenib resistance. Transactivation response element RNA ‐binding protein 2 (TARBP2) is a multifaceted mi RNA biogenesis factor that regulates cancer stem cell ( CSC ) properties. The tumorigenicity and drug resistance of cancer cells are often enhanced due to the acquisition of CSC features. However, the role of TARBP 2 in sorafenib resistance in HCC remains unknown. Our results demonstrate that TARBP 2 is significantly downregulated in sorafenib‐resistant HCC cells. The TARBP 2 protein was destabilized through autophagic–lysosomal proteolysis, thereby stabilizing the expression of the CSC marker protein Nanog, which facilitates sorafenib resistance in HCC cells. In summary, here we reveal a novel mi RNA ‐independent role of TARBP 2 in regulating sorafenib resistance in HCC cells.

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“…A defect in Dicer is one possible mechanism of global downregulated expression of mature miRNAs. Mutations in Dicer were identified in pediatric tumor pleuropulmonary blastoma, Sertoli-Leydig cell tumors, or other tumors [13], [14] and downregulation of DICER is associated with poor prognosis of ovarian cancers and other tumors [11], [15], [16]. These clinical observations, together with experimental results showing the global loss of mature miRNAs induced by Dicer knockdown in vitro and in vivo , demonstrates that Dicer is functionally relevant to oncogenesis [17].…”

Section: Introductionmentioning

confidence: 83%

Unique Haploinsufficient Role of the MicroRNA-Processing Molecule Dicer1 in a Murine Colitis-Associated Tumorigenesis Model

et al. 2013

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A widespread downregulated expression of microRNAs (miRNAs) is commonly observed in human cancers. Similarly, deregulated expression of miRNA-processing pathway components, which results in the reduction of global miRNA expression, may also be associated with tumorigenesis. Here, we show that specific ablation of Dicer1 in intestinal epithelial cells accelerates intestinal inflammation-associated tumorigenesis. This effect was apparent only when a single copy of Dicer1 was deleted, but not with complete Dicer1 ablation. DICER expression and subsequent mature miRNA levels were inversely correlated with the number of intact Dicer1 alleles. Because the expression levels of DICER were retained in tumors and its surrounding tissues even after induction of colitis-associated tumors, the effects of Dicer1 deletion were cell-autonomous. Although the expression levels of representative oncogenes and tumor suppressor genes were in most cases inversely correlated with the expression levels of DICER, some genes were not affected by Dicer1 deletion. Thus, deregulating the delicate balance between the expression levels of tumor-promoting and -suppressive genes may be crucial for tumorigenesis in this unique haploinsufficient case.

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Downregulation of the microRNA biogenesis components and its association with poor prognosis in hepatocellular carcinoma

Cited by 73 publications

References 35 publications

Ochratoxin A induced early hepatotoxicity: new mechanistic insights from microRNA, mRNA and proteomic profiling studies

Ochratoxin A induced early hepatotoxicity: new mechanistic insights from microRNA, mRNA and proteomic profiling studies

TARBP2‐mediated destabilization of Nanog overcomes sorafenib resistance in hepatocellular carcinoma

Unique Haploinsufficient Role of the MicroRNA-Processing Molecule Dicer1 in a Murine Colitis-Associated Tumorigenesis Model

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