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Project description:Background & Aims: Chronic liver inflammation causes continuous liver damage with progressive liver fibrosis and cirrhosis, which may eventually lead to hepatocellular carcinoma (HCC). Whereas, the ten-year incidence for HCC in cirrhotic patients is approximately 20%, many cirrhotic patients remain tumor-free for their entire lives. Therefore, we wanted to clarify the mechanisms defining the different outcomes of chronic liver inflammation. Methods: We designed a longitudinal study comparing the mRNA and miRNA expression profiles in matched non-tumoral liver tissue from patients developing HCC (n = 30) versus patients remaining tumor-free (n = 27). The liver parenchyma was analyzed before and after HCC development in the same patient. Cirrhotic patients remaining tumor-free within a similar time frame served as a control cohort. mRNA expression of genes associated with cancer development and miRNAs were examined by the nCounterNanostring technology. The role of the identified genes involved in HCC development was evaluated by immunohistochemistry and in vitro assays. Results: Comparison of the two cohorts revealed that liver tissue from patients developing HCC displayed activation of NF-B, Insulin receptor and PI3K-AKT pathways, in parallel with increased hepatocyte proliferation and damage. Furthermore, downregulation of miR-579-3p was found as an early step in HCC development. MiR-579-3p directly attenuated PIK3CA expression and consequently AKT and pAKT. In vitro analyses confirmed that miR-579-3p controlled cell proliferation, migration and colony formation. Conclusions: Liver tissues from patients developing HCC revealed a more severe damage to the parenchyma with elevated hepatocyte proliferation. Moreover, miR-579-3p was identified as a potential novel tumor suppressor regulating PI3K-AKT signalling at the early stages of HCC development.
2021-06-20 | GSE116044 | GEO
Project description:Background & Aims: Chronic liver inflammation causes continuous liver damage with progressive liver fibrosis and cirrhosis, which may eventually lead to hepatocellular carcinoma (HCC). Whereas, the ten-year incidence for HCC in cirrhotic patients is approximately 20%, many cirrhotic patients remain tumor-free for their entire lives. Therefore, we wanted to clarify the mechanisms defining the different outcomes of chronic liver inflammation. Methods: We designed a longitudinal study comparing the mRNA and miRNA expression profiles in matched non-tumoral liver tissue from patients developing HCC (n = 30) versus patients remaining tumor-free (n = 27). The liver parenchyma was analyzed before and after HCC development in the same patient. Cirrhotic patients remaining tumor-free within a similar time frame served as a control cohort. mRNA expression of genes associated with cancer development and miRNAs were examined by the nCounterNanostring technology. The role of the identified genes involved in HCC development was evaluated by immunohistochemistry and in vitro assays. Results: Comparison of the two cohorts revealed that liver tissue from patients developing HCC displayed activation of NF-B, Insulin receptor and PI3K-AKT pathways, in parallel with increased hepatocyte proliferation and damage. Furthermore, downregulation of miR-579-3p was found as an early step in HCC development. MiR-579-3p directly attenuated PIK3CA expression and consequently AKT and pAKT. In vitro analyses confirmed that miR-579-3p controlled cell proliferation, migration and colony formation. Conclusions: Liver tissues from patients developing HCC revealed a more severe damage to the parenchyma with elevated hepatocyte proliferation. Moreover, miR-579-3p was identified as a potential novel tumor suppressor regulating PI3K-AKT signalling at the early stages of HCC development.
2021-06-20 | GSE116043 | GEO
Project description:Chronic liver inflammation causes continuous liver damage with progressive liver fibrosis and cirrhosis, which may eventually lead to hepatocellular carcinoma (HCC). Whereas the 10-year incidence for HCC in patients with cirrhosis is approximately 20%, many of these patients remain tumor free for their entire lives. Clarifying the mechanisms that define the various outcomes of chronic liver inflammation is a key aspect in HCC research. In addition to a wide variety of contributing factors, microRNAs (miRNAs) have also been shown to be engaged in promoting liver cancer. Therefore, we wanted to characterize miRNAs that are involved in the development of HCC, and we designed a longitudinal study with formalin-fixed and paraffin-embedded liver biopsy samples from several pathology institutes from Switzerland. We examined the miRNA expression by nCounterNanostring technology in matched nontumoral liver tissue from patients developing HCC (n = 23) before and after HCC formation in the same patient. Patients with cirrhosis (n = 26) remaining tumor free within a similar time frame served as a control cohort. Comparison of the two cohorts revealed that liver tissue from patients developing HCC displayed a down-regulation of miR-579-3p as an early step in HCC development, which was further confirmed in a validation cohort. Correlation with messenger RNA expression profiles further revealed that miR-579-3p directly attenuated phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) expression and consequently protein kinase B (AKT) and phosphorylated AKT. In vitro experiments and the use of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology confirmed that miR-579-3p controlled cell proliferation and cell migration of liver cancer cell lines. Conclusion: Liver tissues from patients developing HCC revealed changes in miRNA expression. miR-579-3p was identified as a novel tumor suppressor regulating phosphoinositide 3-kinase-AKT signaling at the early stages of HCC development.
| S-EPMC9134798 | biostudies-literature
Project description:miR-579-3p controls hepatocellular carcinoma formation by regulating the PI3K-AKT pathway in chronically inflamed liver
| PRJNA476878 | ENA
Project description:miR-579-3p controls hepatocellular carcinoma formation by regulating the PI3K-AKT pathway in chronically inflamed liver (mRNA expression)
| PRJNA476880 | ENA
Project description:miR-579-3p controls hepatocellular carcinoma formation by regulating the PI3K-AKT pathway in chronically inflamed liver (miRNA expression)
| PRJNA476879 | ENA
Project description:Background: The micro-RNA miR-30b-3p has been reported to play a crucial role in several cancers. However, the biological function of miR-30b-3p in hepatocellular carcinoma (HCC) is still unknown. Methods: RT-qPCR was employed to determine the expression of miR-30b-3p in HCC tissues and cells. The MTT assay, colony formation assay, and cell migration and invasion assay were employed to evaluate the role of miR-30b-3p in HCC cells. A dual-luciferase reporter assay was employed to verify the target of miR-30b-3p. Western blotting was employed to determine the expression of key molecular signal transducers along TRIM27-PI3K/Akt axis. Results: Expression of miR-30b-3p was markedly decreased in HCC tissues and cells and positively correlated with higher overall survival. Moreover, miR-30b-3p overexpression significantly repressed cell viability, proliferation, migration, and invasion of HCC cells in vitro. Notably, we demonstrated that miR-30b-3p directly bound to the 3'-untranslated region of tripartite motif containing 27 (TRIM27) mRNA by downregulating the expression of TRIM27, which was demonstrated to be negatively correlated with miR-30b-3p expression. TRIM27 was demonstrated to have an oncogenic role in HCC cells by enhancing cell viability, proliferation, migration, and invasion. Finally, the miR-30-3p-TRIM27-PI3K/Akt axis was shown to play a crucial role in HCC cells in vitro. Conclusion: Our results indicated that miR-30-3p might act as a new biomarker for the future diagnosis and treatment HCC.
| S-EPMC6923265 | biostudies-literature
Project description:Recent studies have shown that miR-494-3p is oncogene and has a central role in many solid tumors; however, the role of miR-494-3p in the progression and prognosis of hepatocellular carcinoma (HCC) remains unknown. In this study, it was found that miR-494-3p was up-regulated in HCC tissues. The high level of miR-494-3p in HCC tumors was correlated with aggressive clinicopathological characteristics and predicted poor prognosis in HCC patients. Functional study demonstrated that miR-494-3p significantly promoted HCC cell metastasis in vitro and vivo. Since phosphoinositide 3-kinase/protein kinase-B (PI3K/AKT) signaling is a basic oncogenic driver in HCC, a potential role of miR-494-3p was explored as well as its target genes in PI3K/AKT activation. Of all the predicted target genes of miR-494-3p, the tumor-suppressor phosphatase and tensin homolog (PTEN) were identified. In conclusion, the data we collected could define an original mechanism of PI3K/AKT hyperactivation and sketch the regulatory role of miR-494-3p in suppressing the expression of PTEN. Therefore, targeting miR-494-3p could provide an effective therapeutic method for the treatment of the disease.
| S-EPMC6041272 | biostudies-literature
Project description:MicroRNAs (miRNAs) play an important role in drug resistance, and it is reported that miR-27a-3p regulated the sensitivity of cisplatin in breast cancer, lung cancer and ovarian cancer. However, the relationship between miR-27a-3p and chemosensitivity of cisplatin in hepatocellular carcinoma (HCC) was unclear, especially the underlying mechanism was unknown. In the present study, we analyzed miR-27a-3p expression levels in 372 tumor tissues and 49 adjacent tissues in HCC samples from TCGA database, and found that the miR-27a-3p was down-regulated in HCC tissues. The level of miR-27a-3p was associated with metastasis, Child-Pugh grade and race. MiR-27a-3p was regarded as a favorable prognosis indicator for HCC patients. Then, miR-27a-3p was overexpressed in HepG2 cell, and was knocked down in PLC cell. Next, we conducted a series of in vitro assays, including MTT, apoptosis and cell cycle assays to observe the biological changes. Further, inhibitor rate and apoptosis rate were detected with pre- and post-cisplatin treatment in HCC. The results showed that overexpression of miR-27a-3p repressed the cell viability, promoted apoptosis and increased the percentage of cells in G0/G1 phase. Importantly, overexpression of miR-27a-3p significantly increased the inhibitor rate and apoptosis rate with cisplatin intervention. Besides, we found that miR-27a-3p added cisplatin sensitivity potentially through regulating PI3K/Akt signaling pathway. Taken together, miR-27a-3p acted as a tumor suppressor gene in HCC cells, and it could be useful for modulating cisplatin sensitivity in chemotherapy.
| S-EPMC8661504 | biostudies-literature
Project description:Background:The hepatocellular carcinoma up-regulated EZH2-associated long non-coding RNA (HEIH) has been identified to act as an oncogene to promote cell tumorigenesis in hepatocellular carcinoma (HCC); however, the roles of HEIH in sorafenib resistance in HCC cells remain elusive. Materials and Methods:The expression of HEIH and microRNA (miR)-98-5p was detected using quantitative real-time polymerase chain reaction. Cell viability, apoptosis, migration and invasion were analyzed using cell counting kit-8 assay, flow cytometry and transwell assay. Western blot was used to measure the levels of apoptosis-related protein and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway-related protein. The interaction between HEIH and miR-98-5p was confirmed by dual-luciferase reporter and RNA immunoprecipitation assay. In vivo experiments were performed using murine xenograft models. Results:HEIH was up-regulated in sorafenib-resistant HCC tissues and cell lines, and HEIH silence weakened sorafenib resistance by suppressing cell viability, invasion and migration, decreasing the IC50 values to sorafenib, and increasing apoptosis in sorafenib-resistant HCC cells in vitro and reinforced the anti-tumor e?ects of sorafenib in vivo. HEIH was a sponge of miR-98-5p, and miR-98-5p inhibition reversed the sorafenib sensitivity induced by HEIH deletion in sorafenib-resistant HCC cells. MiR-98-5p inhibition could activate PI3K/AKT pathway, and enhanced sorafenib resistance by regulating the activation of PI3K/AKT pathway in sorafenib-resistant HCC cells. Besides, HEIH also activated PI3K/AKT pathway through regulating miR-98-5p in sorafenib-resistant HCC cells. Conclusion:HEIH conferred an advantage to sorafenib resistance in HCC by the activation of PI3K/AKT pathway through miR-98-5p, indicating a potential therapeutic strategy for HCC chemotherapy.
| S-EPMC7419617 | biostudies-literature