miR-96 exerts carcinogenic effect by activating AKT/GSK-3β/β-catenin signaling pathway through targeting inhibition of FOXO1 in hepatocellular carcinoma

Yang, Nanying; Zhou, Jinxue; Liu, Qingjun; Han, Feng; Yu, Zujiang

doi:10.1186/s12935-019-0756-7

Cited by 23 publications

(18 citation statements)

References 31 publications

(29 reference statements)

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“…However, we did find that changes in lncZEB1-AS1 expression were closely linked to changes in AKT activation and associated signaling in these cells. Through kinase activity assays and qRT-PCR, we ultimately found that lncZEB1-AS1 can enhance PI3K-AKT signaling in order to upregulate MMP2, MMP7, and MMP9 in HCC cells, thereby promoting tumor metastasis, consistent with prior reports highlighting the importance of AKT signaling in HCC onset and progression [35][36][37][38][39][40][41]. Our data further suggested that lncZEB1-AS1 promotes EGFR upregulation in HC cells, thereby enhanced EGF-but not HGF-mediated activation of PI3K-AKT signaling.…”

Section: Discussionsupporting

confidence: 88%

LncZEB1-AS1 regulates hepatocellular carcinoma bone metastasis via regulation of the miR-302b-EGFR-PI3K-AKT axis

Ma¹,

Wang²,

Li³

et al. 2020

J. Cancer

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In patients with hepatocellular carcinoma (HCC), disease progression and associated bone metastasis (BM) can markedly reduce quality of life. While the long non-coding RNA (lncRNA) zinc finger E-box binding homeobox 1 antisense 1 (ZEB1-AS1) has been shown to function as a key regulator of oncogenic processes in HCC and other tumor types, whether it plays a role in controlling HCC BM remains to be established. In the current study, we detected the significant upregulation of lncZEB1-AS1 in HCC tissues, and we found this expression to be associated with BM progression. When we knocked down this lncRNA in HCC cells, we found that this significantly reduced their migratory, invasive, and metastatic activity both in vitro and in vivo. At a mechanistic level, we found that lncZEB1-AS1 was able to target miR-302b and to thereby increase PI3K-AKT pathway activation and EGFR expression, resulting in the enhanced expression of downstream matrix metalloproteinase genes in HCC cells. In summary, our results provide novel evidence that lncZEB1-AS1 can promote HCC BM through a mechanism dependent upon the activation of PI3K-AKT signaling, thus highlighting a potentially novel therapeutic avenue for the treatment of such metastatic progression in HCC patients.

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Section: Discussionsupporting

confidence: 88%

LncZEB1-AS1 regulates hepatocellular carcinoma bone metastasis via regulation of the miR-302b-EGFR-PI3K-AKT axis

Ma¹,

Wang²,

Li³

et al. 2020

J. Cancer

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“…Furthermore, miRNA-96 expression was reduced in endometrioid adenocarcinoma, papillary thyroid carcinoma, ovarian cancer and hepatocellular carcinoma. 15 In the present study, we first compared expression levels of miRNA-122, miRNA-21 and miRNA-96 in both plasma and exosomes among HCC, cirrhotic and control groups. We found that expression levels of miRNA-21 and miRNA-96 were significantly higher in patients with HCC and of miRNA-122 were significantly lower in HCC compared with cirrhotic patients in both exosomes and plasma.…”

Section: Discussionmentioning

confidence: 99%

“…[10][11][12] Many studies have demonstrated a significant difference in miRNA, especially miRNA-96, miRNA-21 and miRNA-122, expression between hepatocarcinomatous and paracarcinoma tissues, and also affect tumor growth by regulating mRNA protein translation. [13][14][15] Some studies believed that exosomes can be the best choice for non-invasive diagnosis. The reason is because the exosome is not degradable due to protection by cell membranes, so the large amounts of tumor cell information it carries, especially the miRNAs with tumor cell characteristics, are also preserved.…”

Section: Introductionmentioning

confidence: 99%

<p>Exosomal MicroRNAs as Liquid Biopsy Biomarkers in Hepatocellular Carcinoma</p>

Wang

Yang²,

Sun

et al. 2020

OTT

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Hepatocellular carcinoma (HCC) has a high incidence in China and exploring effective ways for early diagnosis is an important method to improve the prognosis of patients with HCC. Additional studies reported that. Some kinds of microRNA (miRNA) in plasma will change accordingly during HCC progress, and this change can be used to diagnose HCC, especially with miRNA-122, miRNA-21 and miRNA-96. We were aiming at investigating the values of the exosomal miRNAs in diagnosis and prognosis for HCC patients. Patients and Methods: Blood samples from 50 patients with HCC and 50 patients with hepatic cirrhosis and 50 healthy volunteers were obtained. The diagnostic accuracy of the plasma and exosomal miRNAs and the comparisons among different groups were measured by the area under the curve (AUC) on receiver operating characteristic (ROC) curve analysis. Results: Expression levels of miRNA-21 and miRNA-96 were significantly higher in patients with HCC and of miRNA-122 were significantly lower in HCC compared with cirrhotic patients in both exosomes and plasma. Among different groups, exosomal miRNA-122, miRNA-21 and miRNA-96 were significantly more accurate in diagnosing HCC than those miRNAs in plasma and the alpha-fetoprotein (AFP) level. The miRNA panel had high accuracy in discriminating HCC from the cirrhosis group (AUC 0.924; 95% CI; sensitivity 82%, specificity 92%) and healthy volunteers' group. Exosomal miRNA-21 and miRNA-96 with low expression and miRNA-122 with high expression could be associated with a patient's survival time. However, the miRNA panel could better predict the HCC patient's survival time compared with each miRNA individually. Conclusion: This study showed that the expression levels of miRNA-122, miRNA-21 and miRNA-96 in exosomes were more significantly changed than those miRNAs in plasma in patients with HCC compared with cirrhotic patients, and the exosomal miRNA panel containing miRNA-122, miRNA-21 and miRNA-96 could be defined as a diagnostic biomarker for patients with HCC. We also conclude that different expression of exosomal miRNAs, especially the miRNA panel, could predict the HCC patient's prognosis.

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“…In the present study, the functional role of miR-96 was investigated using HuCCT1 and HuH28 cell lines; miR-96 promoted the proliferation, migration and invasion of CCA cells. Several genes have been previously validated as direct targets of miR-96 (31,32,37). In hepatocellular carcinoma, the overexpression of miR-96 has been revealed to promote cell proliferation, migration and invasion by inhibiting the expression of SOX6 (32).…”

Section: Discussionmentioning

confidence: 99%

“…Fei et al (31) identified that miR-96 promoted lung cancer cell migration and invasion by targeting the GPC3 gene and that the miR-96/GPC3 axis may represent a therapeutic target for the treatment of non-small cell lung cancer. A recent study by Yang et al (37) indicated that miR-96 is upregulated in hepatocellular carcinoma and exerts a carcinogenic effect by activating the AKT/GSK-3β-catenin signaling pathway by targeting FOXO. In the present study, MTSS1 was identified as a novel target of miR-96.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of microRNA‑96 is associated with poor prognosis and promotes proliferation, migration and invasion in cholangiocarcinoma cells via MTSS1

Yin

Chai

Sun³

et al. 2020

Exp Ther Med

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MicroRNA-96 (miR-96) has been revealed serve an oncogenic role in various types of cancer. However, the role of miR-96 in cholangiocarcinoma (CCA) development and progression is yet to be elucidated. Thus, the aim of the present study was to investigate the role of miR-96 in CCA. The expression pattern of miR-96 in CCA tissues and cell lines was evaluated using reverse transcription-quantitative PCR analysis. Kaplan-Meier curves and Cox regression analyses were conducted to investigate the prognostic significance of miR-96 in CCA. Cell Counting Kit-8 and Transwell assays were performed to identify the functions of miR-96. The association between miR-96 and metastasis suppressor-1 (MTSS1) was verified using a dual-luciferase assay. The results demonstrated that miR-96 expression levels were increased in CCA tissues and cell lines compared with those in adjacent normal tissues and normal human intrahepatic biliary epithelial cell lines, respectively. High expression levels of miR-96 were significantly associated with lymph node metastasis, differentiation and TNM stage. In addition, upregulated expression of miR-96 was associated with a poorer prognosis and was predicted to be a prognostic factor in patients with CCA. Overexpression of miR-96 in vitro promoted CCA cell proliferation, migration and invasion. Additionally, MTSS1 was identified as a direct target of miR-96. The results of the present study indicated the clinical and biological importance of miR-96 as an oncogene in CCA. miR-96 may represent an independent prognostic biomarker and may promote CCA cell proliferation, migration and invasion by targeting MTSS1.

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miR-96 exerts carcinogenic effect by activating AKT/GSK-3β/β-catenin signaling pathway through targeting inhibition of FOXO1 in hepatocellular carcinoma

Cited by 23 publications

References 31 publications

LncZEB1-AS1 regulates hepatocellular carcinoma bone metastasis via regulation of the miR-302b-EGFR-PI3K-AKT axis

LncZEB1-AS1 regulates hepatocellular carcinoma bone metastasis via regulation of the miR-302b-EGFR-PI3K-AKT axis

<p>Exosomal MicroRNAs as Liquid Biopsy Biomarkers in Hepatocellular Carcinoma</p>

Overexpression of microRNA‑96 is associated with poor prognosis and promotes proliferation, migration and invasion in cholangiocarcinoma cells via MTSS1

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