Type 2 diabetes (T2D) is generally regarded as a metabolic disorder disease with various phenotypic expressions. Traditional Chinese medicine (TCM) has been widely used for preventing and treating diabetes. In our study, we demonstrated that Cyclocarya paliurus formula extractum (CPE), a compound of TCM, can ameliorate diabetes in diabetic rats. Transcriptome profiles were performed to elucidate the anti-diabetic mechanisms of CPE on pancreas and liver. Pancreatic transcriptome analysis showed CPE treatment significantly inhibited gene expressions related to inflammation and apoptosis pathways, among which the transcription factors (TFs) nuclear factor κB (NF-κB), STAT, and miR-9a/148/200 may serve as core regulators contributing to ameliorate diabetes. Biochemical studies also demonstrated CPE treatment decreased pro-inflammatory cytokines (tumor necrosis factor alpha [TNF-α], interleukin [IL]-1β, and IL-6) and reduced β cell apoptosis. In liver tissue, our transcriptome and biochemical experiments showed that CPE treatment reduced lipid accumulation and liver injury, and it promoted glycogen synthesis, which may be regulated by TFs Srebf1, Mlxipl, and miR-122/128/192. Taken together, our findings revealed CPE could be used as a potential therapeutic agent to prevent and treat diabetes. It is the first time to combine transcriptome and regulatory network analyses to study the mechanism of CPE in preventing diabetes, giving a demonstration of exploring the mechanism of TCM on complex diseases.

The pediatric T cell acute lymphoblastic leukemia (T-ALL) still remains a cancer with worst prognosis for high recurrence. Massive studies were conducted for the leukemia relapse based on diagnosis and relapse paired samples. However, the initially diagnostic samples may contain the relapse information and mechanism, which were rarely studied. In this study, we collected mRNA and microRNA (miRNA) data from initially diagnosed pediatric T-ALL samples with their relapse or remission status after treatment. Integrated differential co-expression and miRNA-transcription factor (TF)-gene regulatory network analyses were used to reveal the possible relapse mechanisms for pediatric T-ALL. We detected miR-1246/1248 and NOTCH2 served as key nodes in the relapse network, and they combined with TF WT1/SOX4/REL to form regulatory modules that influence the progress of T-ALL. A regulatory loop miR-429-MYCN-MFHAS1 was found potentially associated with the remission of T-ALL. Furthermore, we proved miR-1246/1248 combined with NOTCH2 could promote cell proliferation in the T-ALL cell line by experiments. Meanwhile, analysis based on the miRNA-drug relationships demonstrated that drugs 5-fluorouracil, ascorbate, and trastuzumab targeting miR-1246 could serve as potential supplements for the standard therapy. In conclusion, our findings revealed the potential molecular mechanisms of T-ALL relapse by the combination of co-expression and regulatory network, and they provide preliminary clues for precise treatment of T-ALL patients.

Cytogenetically normal acute myeloid leukemia (CN-AML) presents with diverse outcomes in different patients and is categorized as an intermediate prognosis group. It is important to identify prognostic factors for CN-AML risk stratification. In this study, using the TCGA CN-AML dataset, we found that the scavenger receptor stabilin-1 (STAB1) is a prognostic factor for poor outcomes and validated it in three other independent CN-AML datasets. The high STAB1 expression (STAB1high) group had shorter event-free survival compared with the low STAB1 expression (STAB1low) group in both the TCGA dataset (n = 79; p = 0.0478) and GEO: GSE6891 dataset (n = 187; p = 0.0354). Differential expression analysis between the STAB1high and STAB1low groups revealed that upregulated genes in the STAB1high group were enriched in pathways related to cell adhesion and migration and immune responses. We confirmed that STAB1 suppression inhibits cell growth in KG1a and NB4 leukemia cells. Expression correlation analyses between STAB1 and cancer drug targets suggested that patients in the STAB1low group are more sensitive to the BCL2 inhibitor venetoclax, and we confirmed it in cell lines. In conclusion, we identified STAB1 as a prognostic factor for CN-AML in multiple datasets, explored its underlying mechanism, and provided potential therapeutic indications.

Hepatocellular carcinoma (HCC) is a worldwide malignance, and the underlying mechanisms of this disease are not fully elucidated. In this study, the existence and function of achaete-scute homolog-1 (ASH1)-miR-375-YWHAZ signaling axis in HCC were determined. Our experiments and the Cancer Genome Atlas (TCGA) sequencing data analyses showed that ASH1 and miR-375 were significantly downregulated, whereas YWHAZ was significantly upregulated in HCC. Furthermore, we found that ASH1 positively regulates miR-375, and miR-375 directly downregulates its target YWHAZ. Gain- and loss-of-function study demonstrated ASH1 and miR-375 function as tumor suppressors, whereas YWHAZ acts as an oncogene in HCC. Animal experiment indicated that YWHAZ small interfering RNAs (siRNAs) (si-YWHAZ) delivered by nanoliposomes could suppress the growth of hepatoma xenografts and was well tolerant by nude mice. Further studies revealed that YWHAZ was involved in several protein networks, such as cell autophagy, epithelial-mesenchymal transition (EMT), apoptosis, cell cycle, invasion, and migration. In addition, the patient group with ASH1-high-expression-miR-375-high-expression-YWHAZ-low-expression was correlated with a better clinical prognosis compared with the opposite expression group. In conclusion, we proved the existence of ASH1-miR-375-YWHAZ signaling axis and interpreted its important role in driving HCC tumor progression.

Type 2 diabetes (T2D) is a long-term metabolic disorder disease characterized by high blood sugar and relative lack of insulin. Previous studies have demonstrated that Dendrobium has potent glucose-lowing effects and may serve as add-ons or alternatives to classic medications for T2D prevention and treatment, but the underlying molecular mechanisms were still unclear. We performed biochemical and transcriptional profiling (RNA sequencing [RNA-seq] and microRNA sequencing [miRNA-seq]) analyses on the pancreas and liver of Dendrobium fimbriatum extract (DFE)-fed diabetic rats and control animals. Our sequencing and experimental data indicated that DFE significantly alleviated diabetes symptoms through inhibiting inflammation and preventing islet cell apoptosis in diabetic pancreas. Transcription factors in Stat/nuclear factor κB (NF-κB)/Irf families combined with miR-148a/375/9a served as key regulators in the inflammation and apoptosis pathways under DFE administration. Meanwhile, DFE improved the energy metabolism, lipid transport, and oxidoreductase activity in the liver, and thus decreased lipid accumulation and lipotoxicity-induced hepatocyte apoptosis. Our findings revealed that DFE may serve as a potential therapeutic agent to prevent T2D, and also showed the combination of transcriptome profiling and regulatory network analysis could act as an effective approach for investigating potential molecular mechanisms of traditional Chinese medicine on diseases.

The disruption of epigenetic regulation is common in tumors; the abnormal expression of epigenetic factors leads to cancer occurrence and development. In this study, to investigate the potential function of histone methylation regulators in lung adenocarcinoma (LUAD), we performed differential expression analysis using RNA-seq data downloaded from The Cancer Genome Atlas (TCGA) database, and identified CBX2 and EZH2 as obviously upregulated histone methylation regulators. CBX2 knockdown significantly inhibited LUAD cell growth and metastasis in vitro and in vivo. The combined high expression of CBX2 and EZH2 was an indicator of poor prognosis in LUAD. The inhibition of both CBX2 and EZH2 exerted cooperative suppressive effects on the growth and metastasis of LUAD cells. Mechanistically, we revealed that CBX2 and EZH2 downregulated several PPAR signaling pathway genes and tumor suppressor genes through binding to their promoter cooperatively or separately. Furthermore, knockdown of CBX2 improved the therapeutic efficiency of EZH2 inhibitor on A549 cells. Our study reveals the cooperative oncogenic role of CBX2 and EZH2 in promoting LUAD progression, thereby providing potential targets for LUAD diagnosis and therapy.