E2F1‐mediated AUF1 upregulation promotes HCC development and enhances drug resistance via stabilization of AKR1B10

Zhang, Ting; Guan, Guoxian; Zhang, Jing; Zheng, Heng; Li, Deyao; Wang, Wengong; Lü, Fang; Chen, Xiangmei

doi:10.1111/cas.15272

Cited by 35 publications

(18 citation statements)

References 35 publications

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“…An increasing number of studies have shown that AKR1B10 elevation is responsible for certain cancers. For example, AKR1B10 is significantly upregulated in cancers of the breast, lungs, and liver, and AKR1B10 overexpression facilitates the malignant phenotypes of these cancers [ 35 – 38 ]. In this study, we demonstrated that AKR1B10 exhibits a similar expression pattern and tumor-promoting effects in CCA.…”

Section: Discussionmentioning

confidence: 99%

METTL3 promotes glycolysis and cholangiocarcinoma progression by mediating the m6A modification of AKR1B10

et al. 2022

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Objective N6-methyladenosine (m6A) RNA methylation is involved in governing the mechanism of tumor progression. We aimed to excavate the biological role and mechanism of the m6A methyltransferase METTL3 in cholangiocarcinoma (CCA). Methods METTL3 expression was determined by database and tissue microarray analyses. The role of METTL3 in CCA was explored by loss- and gain-of-function experiments. The m6A target of METTL3 was detected by RNA sequencing. The role of AKR1B10 in CCA was explored, and the association between METTL3 and AKR1B10 was confirmed by rescue experiments. Result METTL3 expression was upregulated in CCA tissue, and higher METTL3 expression was implicated in poor prognoses in CCA patients. Overexpression of METTL3 facilitated proliferation, migration, invasion, glucose uptake, and lactate production in CCA cells, whereas knockdown of METTL3 had the opposite effects. We further found that METTL3 deficiency inhibited CCA tumor growth in vivo. RNA sequencing and MeRIP-qPCR confirmed that METTL3 enhanced AKR1B10 expression and m6A modification levels. Furthermore, METTL3 directly binds with AKR1B10 at an m6A modification site. A CCA tissue microarray showed that AKR1B10 expression was upregulated in CCA tissue and that silencing AKR1B10 suppressed the malignant phenotype mentioned above in CCA. Notably, knockdown of AKR1B10 rescued the tumor-promoting effects induced by METTL3 overexpression. Conclusion Elevated METTL3 expression promotes tumor growth and glycolysis in CCA through m6A modification of AKR1B10, indicating that METTL3 is a potential target for blocking glycolysis for application in CCA therapy.

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Section: Discussionmentioning

confidence: 99%

METTL3 promotes glycolysis and cholangiocarcinoma progression by mediating the m6A modification of AKR1B10

et al. 2022

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“…Hepatic carcinoma (HCC) is a common kind of cancers which seriously hazards human health [ 2 ]. However, increasing researches demonstrate that HCC cells present multiple strategies to achieve drug resistance [ 145 , 146 ]. Accordingly, it is necessary to search effective strategy to treat HCC.…”

Section: Pyroptosis and Cancermentioning

confidence: 99%

Targeted Pyroptosis Is a Potential Therapeutic Strategy for Cancer

Qian

Bai

et al. 2022

Journal of Oncology

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As a type of regulated cell death (RCD) mode, pyroptosis plays an important role in several kinds of cancers. Pyroptosis is induced by different stimuli, whose pathways are divided into the canonical pathway and the noncanonical pathway depending on the formation of the inflammasomes. The canonical pathway is triggered by the assembly of inflammasomes, and the activation of caspase-1 and then the cleavage of effector protein gasdermin D (GSDMD) are promoted. While in the noncanonical pathway, the caspase-4/5/11 (caspase 4/5 in humans and caspase 11 in mice) directly cleave GSDMD without the assembly of inflammasomes. Pyroptosis is involved in various cancers, such as lung cancer, gastric cancer, hepatic carcinoma, breast cancer, and colorectal carcinoma. Pyroptosis in gastric cancer, hepatic carcinoma, breast cancer, and colorectal carcinoma is related to the canonical pathway, while both the canonical and noncanonical pathway participate in lung cancer. Moreover, simvastatin, metformin, and curcumin have effect on these cancers and simultaneously promote the pyroptosis of cancer cells. Accordingly, pyroptosis may be an important therapeutic target for cancer.

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“…HCC is highly heterogeneous and multiple molecular pathways are involved in the development of drug resistance in HCC cells (9). Combining TKIs and immune checkpoint inhibitors (ICIs) is one way to potentially boost effectiveness and minimize treatment resistance in HCC (10).…”

Section: Introductionmentioning

confidence: 99%

Anti-PD-1 antibodies plus lenvatinib in patients with unresectable hepatocellular carcinoma who progressed on lenvatinib: a retrospective cohort study of real-world patients

Zou¹,

Huang²,

Ge³

et al. 2022

J Gastrointest Oncol

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Background: Lenvatinib, a multi-targeted tyrosine kinase inhibitor (TKI), has proven efficacy as the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, there is no standard effective second-line treatment option following progression on lenvatinib therapy. Because of the comprehensive coverage of therapeutic targets of lenvatinib, the remission rate of other TKI treatments in HCC patients resistant to lenvatinib is quite low.Methods: In this study, the effectiveness and safety of anti-programmed cell death protein-1 (PD-1) antibodies plus lenvatinib were assessed in 46 patients between April 2018 and April 2020 at the Zhongshan Hospital, Fudan University, by retrospectively reviewing their clinical data. Patients with unresectable HCC who progressed on lenvatinib were given standard doses of lenvatinib and anti-PD-1 antibodies. They were followed-up every 6-8 weeks with medical imaging and laboratory tests and treatment-related adverse reactions were investigated. Results:The objective response and the disease control rates were 23.9% (11/46) and 71.7% (33/46), respectively by Response Evaluation Criteria in Solid Tumours 1.1 (RECIST). After a median follow-up period of 15.6 [interquartile range (IQR), 11.2-22.0] months, the median progression-free survival (PFS) and overall survival (OS) were 6.9 months [95% confidence interval (CI): 2.1-11.8] and 14.5 months (95% CI: 6.8-22.3), respectively. The most common treatment-related adverse events were anorexia (43.5%), hypothyroidism (43.5%), hypertension (36.9%), fatigue (34.8%), and diarrhea (26.1%). Grade 3/4 events occurred in 16 patients (34.8%). Emotional functioning and overall quality of life were improved significantly following the initiation of anti-PD-1 antibodies plus lenvatinib therapy (fatigue, 4.9±7.5 vs. 11.1±12.7,

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E2F1‐mediated AUF1 upregulation promotes HCC development and enhances drug resistance via stabilization of AKR1B10

Cited by 35 publications

References 35 publications

METTL3 promotes glycolysis and cholangiocarcinoma progression by mediating the m6A modification of AKR1B10

METTL3 promotes glycolysis and cholangiocarcinoma progression by mediating the m6A modification of AKR1B10

Targeted Pyroptosis Is a Potential Therapeutic Strategy for Cancer

Anti-PD-1 antibodies plus lenvatinib in patients with unresectable hepatocellular carcinoma who progressed on lenvatinib: a retrospective cohort study of real-world patients

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