Artemisinin suppresses hepatocellular carcinoma cell growth, migration and invasion by targeting cellular bioenergetics and Hippo-YAP signaling

Li, Yujie; Lü, Jing; Chen, Qin; Han, Shengnan; Shao, Hua; Chen, Pingyi; Jin, Qiumei; Yang, Mingyue; Shangguan, Fugen; Fei, Mingming; Wang, Lu; Liu, Yongzhang; Liu, Naxin; Lü, Bin

doi:10.1007/s00204-019-02579-3

Cited by 34 publications

(20 citation statements)

References 44 publications

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“…16 In one study, DLG2 downregulation reversed the suppressing function of miR-23 on the stem cell proliferation of ovarian cancer. 17 The Hippo signaling pathway, on the other hand, controls the size of organs; it is extensively associated with various tumors, including cancer of the liver, [18][19][20] breast, [21][22][23] lung, 24,25 and rectum. 26,27 DLG2 is an upstream effector of the Hippo signaling pathway, yet its function on CRC has never been studied before.…”

Section: Introductionmentioning

confidence: 99%

Circ0106714 inhibits tumorigenesis of colorectal cancer by sponging miR‐942‐5p and releasing DLG2 via Hippo‐YAP signaling

Yan

Liu

et al. 2020

Molecular Carcinogenesis

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This study aimed to investigate the role of circ0106714-miR-942-5p-discs large homolog 2 (DLG2), a novel interactome, in colorectal cancer (CRC). Circ0106714 was found to be the most significantly downregulated circular RNA in CRC using a bioinformatics method, and we researched whether the ability of circ0106714 to sponge miR-942-5p and release DLG2 could affect CRC development via Hippo-YES-associated protein (YAP) signaling. We first employed qRT-PCR and immunoblotting to detect messenger RNA (mRNA) and protein expression, respectively. Live imaging of mice tumor xenografts was then conducted to study the effect of circ0106714 on tumor progression in vivo. Reporter gene assays were subsequently conducted to verify the predicted targeting relationship between circ0106714, miR-942-5p, and DLG2 mRNA in SW480 and HCT116 cell lines. As well as using flow cytometry for both apoptosis and cell cycle profile analyses, CCK-8 and clone foci formation assays were performed to assess cell survival. Wound healing assay and transwell invasion assay were later carried out to evaluate the migration and invasion of the cell lines. Findings revealed that circ0106714 and DLG2 were significantly downregulated, while miR-942-5p was significantly upregulated in human CRC tissues and cell lines. However, circ0106714 upregulation significantly suppressed tumor progression in vivo and inhibited the malignancy phenotypes of tumor cells in vitro by targeting miR-942-5p. Also discovered in this research was that miR-942-5p could directly target DLG2 mRNA, thus enhancing the malignancy phenotypes of CRC cells. We even found that DLG2 overexpression resulted in enhanced phosphorylation of YAP, a critical downstream effector of DLG2. This downstream effector was demonstrated to have a tumor-suppressive capacity in CRC cell lines. In sum, circ0106714 could suppress CRC by sponging miR-942-5p and releasing DLG2, thus promoting YAP phosphorylation.

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Section: Introductionmentioning

confidence: 99%

Circ0106714 inhibits tumorigenesis of colorectal cancer by sponging miR‐942‐5p and releasing DLG2 via Hippo‐YAP signaling

Yan

Liu

et al. 2020

Molecular Carcinogenesis

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“…Natural products have been discovered as rich and powerful sources for anticancer and antimalarial therapies, including vinblastine from Catharanthus roseus [15,16], paclitaxel or taxol from Taxus brevifolia [17,18], curcurmin from Curcuma longa [19] and artemisinin from Artemisia annua [13,20,21]. Moreover, synthetic compounds were identified to be effective on both cancer cells and Plasmodium, such as gold-or iron-metallocenes [22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic and Anti-Plasmodial Activities of Stephania dielsiana Y.C. Wu Extracts and the Isolated Compounds

et al. 2020

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Natural products remain a viable source of novel therapeutics, and as detection and extraction techniques improve, we can identify more molecules from a broader set of plant tissues. The aim of this study was an investigation of the cytotoxic and anti-plasmodial activities of the methanol extract from Stephania dielsiana Y.C. Wu leaves and its isolated compounds. Our study led to the isolation of seven alkaloids, among which oxostephanine (1) is the most active against several cancer cell lines including HeLa, MDA-MB231, MDA-MB-468, MCF-7, and non-cancer cell lines, such as 184B5 and MCF10A, with IC50 values ranging from 1.66 to 4.35 μM. Morever, oxostephanine (1) is on average two-fold more active against cancer cells than stephanine (3), having a similar chemical structure. Cells treated with oxostephanine (1) are arrested at G2/M cell cycle, followed by the formation of aneuploidy and apoptotic cell death. The G2/M arrest appears to be due, at least in part, to the inactivation of Aurora kinases, which is implicated in the onset and progression of many forms of human cancer. An in-silico molecular modeling study suggests that oxostephanine (1) binds to the ATP binding pocket of Aurora kinases to inactivate their activities. Unlike oxostephanine (1), thailandine (2) is highly effective against only the triple-negative MDA-MB-468 breast cancer cells. However, it showed excellent selectivity against the cancer cell line when compared to its effects on non-cancer cells. Furthermore, thailandine (2) showed excellent anti-plasmodial activity against both chloroquine-susceptible 3D7 and chloroquine-resistant W2 Plasmodium falciparum strains. The structure–activity relationship of isolated compound was also discussed in this study. The results of this study support the traditional use of Stephania dielsiana Y.C. Wu and the lead molecules identified can be further optimized for the development of highly effective and safe anti-cancer and anti-plasmodial drugs.

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“…Hepatocellular carcinoma (HCC), which accounts for ∼85% of all primary liver cancers, is still one of the most fatal diseases worldwide (1). Viral infection, alcohol consumption, smoking, obesity, and gut-derived bacterial translocation have been proven to increase the risk of HCC.…”

Section: Introductionmentioning

confidence: 99%

Identification of Aberrantly Methylated Differentially CpG Sites in Hepatocellular Carcinoma and Their Association With Patient Survival

et al. 2020

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This study aimed to identify aberrantly methylated differentially methylated CpG sites (DMCs) and investigate their prognostic value in hepatocellular carcinoma (HCC). A total of 2,404 DMCs were selected from Gene Expression Omnibus (GEO) and validated by The Cancer Genome Atlas (TCGA). The TCGA cohort was divided into a training cohort and a validating cohort. First, the prognostic model based on six DMCs, including cg08351331, cg02910574, cg09947274, cg17589341, cg24652919, and cg26545968, was constructed based on the least absolute shrinkage and selection operator (LASSO) regression Cox analysis. The area under the curve (AUC) of the DMC-based model was 0.765 in the training cohort and 0.734 in the validating cohort. The accuracy of a model combining the DMC signature and American Joint Committee on Cancer (AJCC) stage, with an AUC of 0.795, was better than that of the DMCs or AJCC stage alone. Second, further analysis revealed that the methylation rate of cg08351331 was negatively associated with the expression of its relative gene, lipopolysaccharide-binding protein (LBP). Besides, the gene expression of LBP was significantly associated with poor overall survival in patients with hepatitis B virus (HBV) infection. Finally, these findings were confirmed by GSE57956 data and our own cohort. In conclusion, we established an accurate DMC-based prognostic model that could be combined with AJCC stage to improve the accuracy of prognostic prediction in HCC. Moreover, our preliminary data indicate that LBP may be a new key factor in HBV-induced HCC initiation through the regulation of its methylation.

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Artemisinin suppresses hepatocellular carcinoma cell growth, migration and invasion by targeting cellular bioenergetics and Hippo-YAP signaling

Cited by 34 publications

References 44 publications

Circ0106714 inhibits tumorigenesis of colorectal cancer by sponging miR‐942‐5p and releasing DLG2 via Hippo‐YAP signaling

Circ0106714 inhibits tumorigenesis of colorectal cancer by sponging miR‐942‐5p and releasing DLG2 via Hippo‐YAP signaling

Cytotoxic and Anti-Plasmodial Activities of Stephania dielsiana Y.C. Wu Extracts and the Isolated Compounds

Identification of Aberrantly Methylated Differentially CpG Sites in Hepatocellular Carcinoma and Their Association With Patient Survival

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