A Functional Screening Identifies a New Organic Selenium Compound Targeting Cancer Stem Cells: Role of c‐Myc Transcription Activity Inhibition in Liver Cancer

Zhou, Junnian; Zhang, Biao; Wang, Haiyang; Wang, Dongxing; Zhang, Mingming; Zhang, Min; Wang, Xiao‐Kui; Fan, Shi‐Yong; Yang, Xu; Zeng, Quan; Jia, Yali; Xi, Jiafei; Nan, Xue; He, Liyun; Zhou, Xin‐Bo; Li, Song; Wang, Zhong; Yue, Wen; Pei, Xuetao

doi:10.1002/advs.202201166

Cited by 14 publications

(13 citation statements)

References 58 publications

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“…We conducted another validation in dataset GSE129671. Among the five most activated transcription factors, MYC [ 52 ] in high NAS group was reported to facilitate cell stemness.…”

Section: Resultsmentioning

confidence: 99%

Scoring model based on the signature of non-m6A-related neoantigen-coding lncRNAs assists in immune microenvironment analysis and TCR-neoantigen pair selection in gliomas

Zhao

et al. 2022

J Transl Med

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Background Small peptides encoded by long non-coding RNAs (lncRNAs) have attracted attention for their various functions. Recent studies indicate that these small peptides participate in immune responses and antigen presentation. However, the significance of RNA modifications remains unclear. Methods Thirteen non-m6A-related neoantigen-coding lncRNAs were selected for analysis from the TransLnc database. Next, a neoantigen activation score (NAS) model was established based on the characteristics of the lncRNAs. Machine learning was employed to expand the model to two additional RNA-seq and two single-cell sequencing datasets for further validation. The DLpTCR algorithm was used to predict T cell receptor (TCR)-peptide binding probability. Results The non-m6A-related NAS model predicted patients’ overall survival outcomes more precisely than the m6A-related NAS model. Furthermore, the non-m6A-related NAS was positively correlated with tumor cells’ evolutionary level, immune infiltration, and antigen presentation. However, high NAS gliomas also showed more PD-L1 expression and high mutation frequencies of T-cell positive regulators. Interestingly, results of intercellular communication analysis suggest that T cell-high neoplastic cell interaction is weaker in both of the NAS groups which might arise from decreased IFNGR1 expression. Moreover, we identified unique TCR-peptide pairs present in all glioma samples based on peptides encoded by the 13 selected lncRNAs. And increased levels of neoantigen-active TCR patterns were found in high NAS gliomas. Conclusions Our work suggests that non-m6A-related neoantigen-coding lncRNAs play an essential role in glioma progression and that screened TCR clonotypes might provide potential avenues for chimeric antigen receptor T cell (CAR-T) therapy for gliomas.

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“…We conducted another validation in dataset GSE129671. Among the five most activated transcription factors, MYC [ 52 ] in high NAS group was reported to facilitate cell stemness.…”

Section: Resultsmentioning

confidence: 99%

Scoring model based on the signature of non-m6A-related neoantigen-coding lncRNAs assists in immune microenvironment analysis and TCR-neoantigen pair selection in gliomas

Zhao

et al. 2022

J Transl Med

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“…Overall, EIF5A2 is the key gene that simultaneously regulates the interaction between EMT and stemness. Meanwhile, there are many common signaling pathways between EMT and stemness, such as PI3K/Akt, Wnt/β-catenin and TGF-β [ 33 , 34 , 35 ]. Because of this, through KEGG and GSVA enrichment analyses, we realized that EIF5A2/PI3k/Akt was the key signaling pathway regulating HCC EMT and stemness.…”

Section: Discussionmentioning

confidence: 99%

Genistein Restricts the Epithelial Mesenchymal Transformation (EMT) and Stemness of Hepatocellular Carcinoma via Upregulating miR-1275 to Inhibit the EIF5A2/PI3K/Akt Pathway

Yang

Jiang

Kong

et al. 2022

Biology

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Purpose: Genistein is a natural phytoestrogen with various antitumor effects. In recent years, some microRNAs (miRNA) in cancer cells have been reported to be regulated by genistein. Our study focused on exploring the mechanisms of miRNA upregulation to inhibit the epithelial mesenchymal transformation (EMT) and stemness of hepatocellular carcinoma (HCC). Patients and Methods: MiR-1275 was discovered by the transcriptome sequencing of miRNA expression profiles in HepG2 cells treated with genistein or DMSO as a control. Then, we performed series functional experiments in vitro and vivo to explore the relationship between genistein and miR-1275 in HCC. The target gene (Eukaryotic initiation factor 5A2, EIF5A2) of miR-1275 was predicted by databases and finally determined by a dual luciferase reporter assay. The downstream signaling pathway of EIF5A2 was assessed by bioinformatics analysis and Western blot. Results: the inhibition of genistein on the viability of HCC cells was enhanced by the increase in treatment time and dose, but it had no obvious inhibitory effect on normal hepatocytes (QSG-7701). Through qRT-PCR and transcriptome sequencing, we discovered that miR-1275 was lowly expressed in HCC, and it can be raised by genistein. The overall survival (OS) and recurrence-free survival (RFS) of HCC patients with lowly expressed miR-1275 were lower than those of those with high expression levels. In vitro and vivo experiments exhibited that genistein and the overexpression of miR-1275 can both significantly suppress the proliferation, migration, invasion, metastasis, EMT and stemness of HCC. Moreover, the inhibition can be further enhanced when miR-1275 mimic and genistein exist together. Finally, we demonstrated that miR-1275 can inhibit the epithelial mesenchymal transformation (EMT) and stemness of HCC via inhibiting the EIF5A2/PI3K/Akt pathway. Conclusion: Our findings proved that genistein can inhibit the EIF5A2/PI3K/Akt pathway by upregulating miR-1275 so as to attenuate the EMT and stemness of HCC cells to restrict their progression and metastasis.

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“…The Notch signaling pathway plays a crucial role in the regulation of stem cell properties in HCC [44] ,…”

Section: Discussionmentioning

confidence: 99%

The stromal-tumor amplifying STC1-Notch1 feedforward signal promotes the stemness of hepatocellular carcinoma

Bai

Zhao

Chen

et al. 2022

Preprint

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Background Cancer associated fibroblasts (CAFs), an important component of the tumor microenvironment (TME), play crucial roles in tumor stemness. Stanniocalcin-1 (STC1) was found secreted by CAFs in various cancers, but its main source and its role in hepatocellular carcinoma (HCC) was still unclear. Methods The serum and intracellular expression levels of STC1 were detected by ELISA and western blot. The role of CAFs-derived STC1 in HCC stemness was probed by sphere formation, sorafenib resistance, colony formation, and transwell migration and invasion assays in vitro and orthotopic liver xenograft tumor model in vivo. An HCC tissue microarray containing 72 samples was used to identify the STC1 and the Notch1 in HCC tissues. Co-immunoprecipitation (CoIP) and dual-luciferase reporter assay were performed to further explore the underlying mechanisms. ELISA assays were used to detect the serum concentration of STC1 in HCC patients. Results We demonstrated that CAFs were the main source of STC1 in HCC and that CAFs-derived STC1 promoted HCC stemness through the activation of the Notch signaling pathway. In HCC patients, the expression of STC1 was positively correlated with poor prognosis and the Nocth1 expression. Co-IP assay showed that STC1 directly bound to Notch1 receptors to activate the Notch signaling pathway, thereby promoting the stemness of HCC. Our data further demonstrated that STC1 was a direct transcriptional target of CSL in HCC cells. Furthermore, ELISA revealed that the serum STC1 concentration was higher in patients with advanced liver cancer than patients with early liver cancer. Conclusions CAFs-derived STC1 promoted HCC stemness via the Notch signaling pathway. STC1 might serve as a potential biomarker for the prognostic assessment of HCC, and the stromal-tumor amplifying STC1-Notch1 feedforward signal could provide an effective therapeutic target for HCC patients.

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A Functional Screening Identifies a New Organic Selenium Compound Targeting Cancer Stem Cells: Role of c‐Myc Transcription Activity Inhibition in Liver Cancer

Cited by 14 publications

References 58 publications

Scoring model based on the signature of non-m6A-related neoantigen-coding lncRNAs assists in immune microenvironment analysis and TCR-neoantigen pair selection in gliomas

Scoring model based on the signature of non-m6A-related neoantigen-coding lncRNAs assists in immune microenvironment analysis and TCR-neoantigen pair selection in gliomas

Genistein Restricts the Epithelial Mesenchymal Transformation (EMT) and Stemness of Hepatocellular Carcinoma via Upregulating miR-1275 to Inhibit the EIF5A2/PI3K/Akt Pathway

The stromal-tumor amplifying STC1-Notch1 feedforward signal promotes the stemness of hepatocellular carcinoma

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