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Transcriptome Analysis Reveals Potential Protective Effects and Biomarkers of Pien Tze Huang on CCl4-induced Liver Cancer (miRNA)

ABSTRACT: Pien Tze Huang (PZH) is a traditional Chinese medicinal formula that has been extensively used in Asia for the treatment of liver diseases. We created two groups of liver cancer mouse models induced by carbon tetrachloride (CCl4): one group received treatment with PZH and the other did not receive any treatment. In the non-PZH treated group, we observed a significant increase in liver function indices including albumin (ALB), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Histological examination using hematoxylin and eosin (HE) staining revealed inflammation around the hepatic vein in the non-PZH treated group. Furthermore, Masson's trichrome staining demonstrated the presence of blue-stained collagen fibers around the hepatic vein in the non-PZH treated group. These findings suggest that PZH may have therapeutic effects on liver inflammation and cancer. To further explore the molecular mechanisms of PZH's action, we conducted mRNA, long non-coding RNA (lncRNA), circular RNA (circRNA), and microRNA (miRNA) sequencing to identify potential drug targets at the transcriptome level. We identified 478 differentially expressed protein-coding transcripts and 68 differentially expressed lncRNA transcripts. Our study provides insights into potential transcriptional therapeutic targets for the clinical use of PZH in treating liver diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE268337 | GEO | 2024/05/26

REPOSITORIES: GEO

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Project description:Background: N-acetylcysteine (NAC), a scavenger of free radicals, possesses strong capability to improve high fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in mice. However, the underlying mechanism(s) of NAC-ameliorated NAFLD are still not fully illustrated. This study was designed to clarify the involvement of long chain non-coding RNAs (lncRNAs) in the beneficial effects of NAC on NAFLD in HFD-induced obese mice. Methods: C57BL/6J mice were arranged into normal fat diet (10% energy from fat), HFD (45% energy from fat), and HFD plus NAC (2 g/L in drinking water) groups, respectively. After 14-week intervention, the role of NAC was determined by immunohistochemistry and biochemical indexes in both plasma and liver. The profiles of hepatic lncRNAs were analyzed by whole transcriptome sequencing, and were further verified by quantitative real-time polymerase chain reaction (qRT-PCR). Meanwhile, the gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analyses were carried out to identify the functions of candidate lncRNAs. Furthermore, lncRNA-related ceRNA network was constructed in combination with miRNA and mRNA profiles by Cytoscape software. Results: NAC treatment obviously rescued the deleterious alterations induced by HFD, including body and liver weight, hepatic triglyceride (TG), plasma alanine aminotransferase (ALT), plasma aspartate transaminase (AST), and liver histomorphology (H&E and Oil red O staining). Through whole transcriptome sequencing technology, 52167 (50758 known and 1409 novel) lncRNAs were detectable in liver samples. Our data revealed that the expressions of 175 lncRNAs were significantly changed by HFD but reversed by NAC treatment through cross-comparison. Among those lncRNAs, 5 lncRNAs, including lncRNA-NONMMUT148902.1 (NO_902.1), lncRNA-XR_001781798.1 (XR_798.1), lncRNA-NONMMUT141720.1 (NO_720.1), lncRNA-XR_869907.1 (XR_907.1), and lncRNA-ENSMUST00000132181 (EN_181), were selected based on the absolute value of log2 fold change (FC) being greater than 4, P-value ＜ 0.01, and P-adjust ＜ 0.01. Further qRT-PCR identified that lncRNA-NO_902.1, lncRNA-XR_798.1, and lncRNA-EN_181 were dramatically decreased by HFD while rescued by NAC treatment, consistent with the RNA-sequencing. Finally, we further screened and constructed a ceRNA network, including lncRNA-EN_181, 3 miRNAs, and 13 mRNAs, which was associated with the beneficial role of NAC in NAFLD. Conclusions: This study identified for the first time that lncRNA-EN_181 might be a potential target in NAC-ameliorated NAFLD. The finding enhanced our understanding of biological mechanisms in the beneficial role of NAC.

Project description:Aim: The aim of this study is to explore the impact of Pien Tze Huang (PZH) on enhancing T cell cytotoxicity by modulating colorectal cancer stem cell (CRC-CSC) markers, programmed death protein ligand-1 (PD-L1), and the transcription factor signal transducer and activator of transcription 3 (STAT3) protein expression in vivo, ex vivo, and in vitro. Methods: HCT116, HCT15, and SW480 cell lines were subjected to treatment with PZH, followed by assessment of cell viability and stemness through CCK8 and spheroid formation assays. Western blot and immunofluorescence techniques were employed to evaluate the expression levels of stem cell markers (DCLK1, CD133, CD44, MET, and LGR5), PD-L1, and STAT3 across three CRC cell lines and five patient-derived organoids (PDOs). Flow cytometry and western blot analyses were utilized to validate T cell expansion from both donors and CRC patients. CRC cells and CRC-PDOs, pre-treated with PZH, were co-cultured with expanded T cells from both donor and autologous peripheral blood mononuclear cells (PBMCs) respectively. The viability of CRC cells and PDOs was evaluated through Calcein-AM staining to measure fluorescence intensity and cell count following co-culture. In the syngeneic MC38 C57BL/6 xenograft model, tumor growth curve and body weight were monitored subsequent to treatment with PZH, anti-PD-1, and PZH combined with anti-PD-1. Immunohistochemistry was performed to assess protein levels of CD133, CD44, STAT3, PD-L1, CD8, and IL-6R in tumor tissue. Results: The effectiveness of PZH in reducing CRC cell viability and suppressing stemness markers, such as LGR5, CD44, MET, DCLK1, and CD133, is evident. PZH also displayed inhibitory effects on tumorigenesis in five CRC-PDOs, with varying sensitivity across cases (3 sensitive and 2 less sensitive). Moreover, PZH enhanced the cytotoxicity of donor T cells against CRC cells and rectified the cytotoxic deficiency or bolstered the cytotoxicity of autologous T cells against CRC-PDOs by downregulating PD-L1 and STAT3 protein expressi Conclusion: PZH enhances T cell-mediated killing effect by inhibiting CRC stem cell markers, PD-L1, and STAT3. Key Words: Pien Tze Huang, patient-derived organoid, colorectal cancer stem cells, programmed death protein ligand-1, signal transducer and activator of transcription 3

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Transcriptome Analysis Reveals Potential Protective Effects and Biomarkers of Pien Tze Huang on CCl4-induced Liver Cancer (miRNA)

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