VIRMA/IGF2BP3-mediated ANLN upregulation promotes intrahepatic cholangiocarcinoma growth by forming a positive
Jiajun Zhang1, Ning Huang1, Lin-Rui Gao2
1Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Abstract:
The prognosis of patients with intrahepatic cholangiocarcinoma (ICC) remains poor owing to the lack of effective targeted therapeutic strategies. Thus, the exploration of the molecular pathogenesis of ICC is urgently required. The cytoskeleton protein, anillin (ANLN), has been reported to contribute to various tumor growth by participating in cytokinesis via RhoA signaling. However, the exact physiological role and potential regulatory mechanism of ANLN in ICC are still not well understood. Based on spindle-related genes, integrated bioinformatic analyses identified ANLN as a potential candidate target for ICC. ANLN was elevated in ICC and predicted worse survival. Mechanistically, VIRMA-mediated m6A modification and IGF2BP3-dependent interaction collectively accounted for the upregulation of ANLN by maintaining its mRNA stability. Furthermore, the combination of ANLN and VIRMA or IGF2BP3 offered a greater predictive value than each marker alone in a large ICC cohort. Functional studies indicated that ANLN was involved in cancer cell proliferation and cell cycle. ANLN knockdown induced cytokinesis failure, DNA damage, and apoptosis in ICC cells. In addition to discovering the crucial role of ANLN in cytokinesis via RhoA activation, we also illustrated that ANLN restrained the Hippo pathway by enhancing the activity of RhoA signaling, which together contributed to ANLN-mediated tumor-promoting effects on ICC. Furthermore, YAP1-TEAD1 transcriptionally activated ANLN, subsequently establishing a self-reinforcing loop between ANLN and Hippo pathway, which was mediated by RhoA signaling as an intermediate regulatory node. Importantly, two clinical drugs, the RhoA inhibitor simvastatin and the YAP1/TEAD inhibitor verteporfin were determined to be the disruptors of this feed-forward signaling axis, inhibiting ICC tumor growth. These findings reveal the vital function of ANLN in ICC growth and provide promising treatment strategies for ICC.
Insights
Anillin (ANLN) drives intrahepatic cholangiocarcinoma (ICC) growth by regulating cell division and the Hippo pathway. Targeting ANLN with drugs like simvastatin or verteporfin shows promise for treating ICC.
Area of Science:
- Oncology
- Molecular Biology
- Bioinformatics
Background:
- Intrahepatic cholangiocarcinoma (ICC) has a poor prognosis due to limited targeted therapies.
- Understanding ICC's molecular pathogenesis is crucial for developing effective treatments.
- The role of anillin (ANLN), a cytoskeleton protein, in ICC is not well understood.
Purpose of the Study:
- To investigate the role and regulatory mechanisms of ANLN in ICC.
- To identify ANLN as a potential therapeutic target for ICC.
- To explore the interplay between ANLN, RhoA signaling, and the Hippo pathway in ICC.
Main Methods:
- Integrated bioinformatic analyses using spindle-related genes.
- In vitro functional studies including gene knockdown and cell-based assays.
- Analysis of clinical ICC cohorts to assess prognostic and predictive values.
Main Results:
- ANLN is upregulated in ICC and correlates with worse survival.
- VIRMA-mediated m6A modification and IGF2BP3 stabilize ANLN mRNA.
- ANLN promotes ICC proliferation, cell cycle progression, and restrains the Hippo pathway via RhoA activation.
- A self-reinforcing loop exists between ANLN and the Hippo pathway, regulated by RhoA signaling.
- Simvastatin and verteporfin inhibit ICC growth by disrupting this signaling axis.
Conclusions:
- ANLN plays a critical role in ICC progression by influencing cytokinesis and the Hippo pathway.
- Combined detection of ANLN, VIRMA, or IGF2BP3 enhances ICC prediction.
- Targeting the ANLN-mediated signaling axis with existing drugs offers a potential therapeutic strategy for ICC.
More Related Videos
06:38An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
11:32Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
Published on: March 27, 2020
Related Concept Videos
Regulation of Angiogenesis and Blood Supply
mTOR Signaling and Cancer Progression
The mTOR pathway or the...
Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
The Ras Gene
Ras is a...
PI3K/mTOR/AKT Signaling Pathway
Abnormal Proliferation
