Correction: Lycorine hydrochloride inhibits cell proliferation and induces apoptosis through promoting FBXW7-MCL1 axis in gastric cancer.
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SUBMITTER: Li C
PROVIDER: S-EPMC9578188 | biostudies-literature | 2022 Oct
REPOSITORIES: biostudies-literature
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Correction: Lycorine hydrochloride inhibits cell proliferation and induces apoptosis through promoting FBXW7-MCL1 axis in gastric cancer.
Li Chongyang C Deng Chaowei C Pan Guangzhao G Wang Xue X Zhang Kui K Dong Zhen Z Zhao Gaichao G Tan Mengqin M Hu Xiaosong X Shi Shaomin S Du Juan J Ji Haoyan H Wang Xiaowen X Yang Liqun L Cui Hongjuan H
Journal of experimental & clinical cancer research : CR 20221018 1
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Project description:BackgroundLycorine hydrochloride (LH), an alkaloid extracted from the bulb of the Lycoris radiata, is considered to have anti-viral, anti-malarial, and anti-tumorous effects. At present, the underlying mechanisms of LH in gastric cancer remain unclear. MCL1, an anti-apoptotic protein of BCL2 family, is closely related to drug resistance of tumor. Therefore, MCL1 is considered as a potential target for cancer treatment.MethodsThe effect of LH on gastric cancer was assessed in vitro (by MTT, BrdU, western blotting…) and in vivo (by immunohistochemistry).ResultsIn this study, we showed that LH has an anti-tumorous effect by down-regulating MCL1 in gastric cancer. Besides, we unveiled that LH reduced the protein stability of MCL1 by up-regulating ubiquitin E3 ligase FBXW7, arrested cell cycle at S phase and triggered apoptosis of gastric cancer cells. Meanwhile, we also demonstrated that LH could induce apoptosis of the BCL2-drug-resistant-cell-lines. Moreover, PDX (Patient-Derived tumor xenograft) model experiment proved that LH combined with HA14-1 (inhibitor of BCL2), had a more significant therapeutic effect on gastric cancer.ConclusionsThe efficacy showed in our data suggests that lycorine hydrochloride is a promising anti-tumor compound for gastric cancer.
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Project description:The ubiquitin ligase F-box and WD repeat domain-containing 7 (FBXW7) is responsible for degrading diverse oncoproteins and is considered a tumor suppressor in many human cancers. Inhibiting FBXW7 enhances the malignant potential of several cancers. In this study, we aimed to investigate the role of FBXW7 in cholangiocarcinoma. We found that FBXW7 expression was associated with clinicopathological outcomes in cholangiocarcinoma patients. Both disease-free and overall survival were significantly worse in the low-FBXW7 group than in the high-FBXW7 group (P = .001 and P < .001, respectively). Multivariate analysis with the Cox proportional hazards model indicated that FBXW7 was the most important independent prognostic factor for disease-free (P = .006) and overall (P = .0004) survival. We also showed that the two FBXW7 substrates, NOTCH1 and myeloid cell leukemia sequence 1 (MCL1), regulate cholangiocarcinoma progression. Depletion of FBXW7 resulted in NOTCH1 accumulation and increased cholangiocarcinoma cell migration and self-renewal. Interestingly, when cells were stimulated with cis-diamminedichloridoplatinum(II) (cisplatin), FBXW7 suppression induced MCL1 upregulation, which reduced the sensitivity of cholangiocarcinoma cells to apoptosis, indicating that FBXW7-mediated ubiquitylation is context-dependent. These results indicate that FBXW7 modulates the malignant potential of cholangiocarcinoma through independent regulation of NOTCH1 and MCL1.
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Project description:Lycorine hydrochloride (LH) is an active ingredient sourced from the medicinal herb Lycoris radiata. Previous studies have suggested that LH exerts tumor suppression activity in several human cancers. However, the anti-cancer effect of LH in melanoma and the potential molecular mechanisms still need to be further studied. p21Cip1/WAF1, unlike its traditional cyclin-dependent kinase (CDK) inhibitor role, is believed to act as an oncogene under certain cellular conditions. In this research, an increased expression of p21Cip1/WAF1 was found in human melanoma tissues and positively related to the tumor invasion depth. High level of p21Cip1/WAF1 was found to correlate with bad outcomes of melanoma patients by Kaplan-Meier survival analysis. Functional experiments demonstrated that the proliferation, migration and invasion ability of A375 and MV3 melanoma cells was powerfully inhibited by LH through inducing S phase cell cycle arrest and regulating epithelial-mesenchymal transition (EMT). In NOD/SCID mice model, LH effectively inhibited the xenograft tumor growth and lung metastasis of A375 cells. Further research revealed that LH reduced p21Cip1/WAF1 protein by accelerating its ubiquitination. Importantly, the LH-induced suppression of cell proliferation and metastasis was rescued by p21Cip1/WAF1 overexpression, both in vitro an in vivo. Taken together, LH, which suppresses the proliferation and metastasis of melanoma cells via down-regulating p21Cip1/WAF1, is expected to be developed as an effective medicine for melanoma therapy.
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Project description:BackgroundHepatocellular carcinoma (HCC) is one of the most malignant tumors and has a poor 5-year survival rate. Family with sequence similarity 83, member D (FAM83D) is characterized as an oncogenic gene related to cell proliferation in many tumors, but the role and underlying mechanism of FAM83D in the development of HCC are still unclear.MethodsFAM83D expression profiles and clinicopathological data were obtained from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC). Additionally, 2 data sets from the Gene Expression Omnibus (GEO) database were used to further validate the FAM83D profile in HCC. We then downregulated the expression of FAM83D in HCC cells transfected with FAM83D small-interfering ribonucleic acid (siRNA) and upregulating its expression by FAM83D-overexpression transfection for further in vitro studies.ResultsTCGA and the GEO databases showed that FAM83D was significantly more upregulated in tumor tissues than non-tumor tissues. The high expression of FAM83D in HCC is associated with poor prognostic clinical factors. The knockdown of FAM83D in SNU449 and HUH7 cells in vitro impaired cell proliferation and migration, and promoted apoptosis, while the overexpression of FAM83D in BEL7402 cells had the opposite effect. Further, combined transfection with FBXW7 siRNA or MCL1-overexpression reversed the role of FAM83D knockdown on cell proliferation, migration, and apoptosis in vitro, while FBXW7 expression was negatively correlated with both the FAM83D and MCL1 levels in TCGA-LIHC patients.ConclusionsFAM83D played a significant role in HCC progression by enhancing cell proliferation and migration and inhibiting apoptosis, which may have been caused by the inhibition of the FBXW7/MCL1 signaling pathway. Thus, FAM83D may be a promising therapeutic target for HCC.
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Project description:Circular RNAs, noncoding RNAs, have attracted much attention in various human tumor research fields. They regulate the development of various human cancers via microRNA sponges. This study aimed to assess the molecular mechanism of circSLC30A7 in hepatocellular carcinoma (HCC). In our study, we identified that circSLC30A7 was significantly downregulated in HCC cell lines and tissues. Furthermore, gain and loss function experiments were conducted to elucidate the biological functions of circSLC30A7 in HCC cell lines. Mechanistically, circSLC30A7 sponged miR-767-5p, inhibiting the expression of its downstream protein, FBXW7. In summary, this study revealed that circSLC30A7 is an essential tumor suppressor that inhibits HCC tumorigenesis through the miR-767-5p/FBXW7/NOTCH1 axis. Taken together, circSLC30A7 reduces HCC malignancy and can be a biomarker for HCC management.
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