Aberrant hedgehog signaling is responsible for the highly invasive behavior of a subpopulation of hepatoma cells

Fan, Yi; Ding, Jia; Nguyen, Samantha; Liu, X. J.; Xu, Gang; Zhou, Hang; Duan, Na; Yang, Sheng; Zern, Mark Α.; Wu, Jian

doi:10.1038/onc.2015.67

Cited by 36 publications

(35 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the present study, we compared the phenotypic features of a newly established subpopulation of Huh-7-DN with the previously reported Huh-7-trans subpopulation, 14 and other subpopulations or hepatoma cells, and characterized their sensitivity to sorafenib, LDE225 and another Hh inhibitor, itraconazole. The latter is an antifungal agent, and was defined as a potent Hh inhibitor that targets SMO and is distinct from other Hh inhibitors, such as LDE225 or cyclopamine.…”

Section: Discussionmentioning

confidence: 99%

“…Drug resistance has apparently developed in these cells because LDE225 has been shown to be effective at nM levels. 14,30 To further verify the effect of Gli-2 on ABCC1 expression, we used RNA interference (RNAi) and suppressed Gli-2 expression with transduction of a lentiviral-particle-harboring shRNA against Gli-2 gene in both Huh-7-DN and Huh-7-trans cells, and used cells transduced with lentiviral particles harboring scrambled shRNA as a control (Supplementary Figure 3). Our data demonstrate that shRNA against Gli-2 reduced Gli-2 gene expression by 50-70% at mRNA levels in two clones, and nearly 25-30% reduction at protein levels in both Huh-7-trans and Huh-7-DN cells (Po0.05-0.01).…”

Section: Discussionmentioning

confidence: 99%

“…Specific protein bands were visualized by the enhanced chemiluminescent reagent (Tanon, Shanghai, China) as previously reported. 14 …”

Section: Materials and Methods Cell Culture And Reagentsmentioning

confidence: 99%

“…The Huh-7-trans subpopulation was isolated using Matrigel invasion transwell selection as we previously described. 14 Immunofluorescent Staining CD133 + /EpCAM + , CD133 − /EpCAM − , Huh-7-DN, and Huh-7-trans subpopulations were seeded on coverslips and fixed in 4% buffered paraformaldehyde. Then cells on coverslips were incubated with primary antibodies against Gli-1, E-cadherin, vimentin, Gli-2, and ABCC1 overnight at 4 1C, and were stained with secondary antibodies (Alexa Fluor 488-conjugated donkey anti-mouse IgG or Alexa Fluor 594/488-conjugated donkey anti-rabbit IgG) as we previously described.…”

Section: Materials and Methods Cell Culture And Reagentsmentioning

confidence: 99%

“…Overexpression of Hh pathway molecules, such as sonic Hh, PTCH1, SMO, and Gli-1/2, has been reported in 60-70% of HCC specimens, 11,12 and dysregulated expression of Hh molecules is one of disordered signaling mechanisms crucial for hepatic carcinogenesis 13 and highly metastatic behavior of HCC. 14 Hh signaling inhibitors, such as vismodegib (GDC--0449) and sonidegib (LDE225), are approved for the treatment of advanced basal cell carcinoma; 15 and sonidegib is in phase I-II clinical trials for the treatment of a variety of malignancies, including esophageal, pancreatic, ovarian cancers, and hepatocellular carcinoma. 16 However, whether abnormal hedgehog signaling has a critical role in modulating drug resistance through ABC transporter molecules has not been thoroughly investigated.…”

mentioning

confidence: 99%

See 4 more Smart Citations

Hedgehog signaling pathway affects the sensitivity of hepatoma cells to drug therapy through the ABCC1 transporter

Ding

Xiao

Zou

et al. 2017

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Specific protein bands were visualized by the enhanced chemiluminescent reagent (Tanon, Shanghai, China) as previously reported. 14 …”

Section: Materials and Methods Cell Culture And Reagentsmentioning

confidence: 99%

Section: Materials and Methods Cell Culture And Reagentsmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Hedgehog signaling pathway affects the sensitivity of hepatoma cells to drug therapy through the ABCC1 transporter

Ding

Xiao

Zou

et al. 2017

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

Genomic alterations of oligodendrogliomas at distant recurrence

Liu

Guo

et al. 2023

Cancer Medicine

View full text Add to dashboard Cite

BackgroundOligodendroglioma is known for its relatively better prognosis and responsiveness to radiotherapy and chemotherapy. However, little is known about the evolution of genetic changes as oligodendroglioma progresses.MethodsIn this study, we evaluated gene evolution invivo during tumor progression based on deep whole‐genome sequencing data (ctDNA). We analyzed longitudinal genomic data from six patients during tumor evolution, of which five patients developed distant recurrence.ResultsWhole‐exome sequencing demonstrated that the rate of shared mutations between the primary and recurrent samples was relatively low. In two cases, even well‐known major driver mutations in CIC and FUBP1 that were detected in primary tumors were not detected in the relapse samples. Among these cases, two patients had a conversion from the IDH mutation in the originating state to the IDH1 wild state during the process of gene evolution under chemotherapy treatment, indicating that the cell phenotype and genetic characteristics of oligodendroglioma may change during tumor evolution. Two patients received long‐term temozolomide (TMZ) treatment before the operation, and we found that recurrence tumors harbored mutations in the PI3K/AKT and Sonic hedgehog (SHh) signaling pathways. Hypermutation occurred with mutations in MMR genes in one patient, contributing to the rapid progression of the tumor.ConclusionOligodendroglioma displayed great spatial and temporal heterogeneity during tumor evolution. The PI3K/AKT and SHh signaling pathways may play an important role in promoting treatment resistance and distant relapse during oligodendroglioma evolution. In addition, there was a tendency to increase the degree of tumor malignancy during evolution. Distant recurrence may be a later event duringoligodendroglioma progression. ClinicalTrials.gov, Identifier: NCT05512325.

show abstract

JCAD deficiency delayed liver regenerative repair through the Hippo–YAP signalling pathway

Zhang,

Yang,

Xie

et al. 2024

Clinical & Translational Med

Self Cite

View full text Add to dashboard Cite

Background and aimsLiver regeneration retardation post partial hepatectomy (PH) is a common clinical problem after liver transplantation. Identification of key regulators in liver regeneration post PH may be beneficial for clinically improving the prognosis of patients after liver transplantation. This study aimed to clarify the function of junctional protein‐associated with coronary artery disease (JCAD) in liver regeneration post PH and to reveal the underlying mechanisms.MethodsJCAD knockout (JCAD‐KO), liver‐specific JCAD‐KO (Jcad△Hep) mice and their control group were subjected to 70% PH. RNA sequencing was conducted to unravel the related signalling pathways. Primary hepatocytes from KO mice were treated with epidermal growth factor (EGF) to evaluate DNA replication. Fluorescent ubiquitination‐based cell cycle indicator (FUCCI) live‐imaging system was used to visualise the phases of cell cycle.ResultsBoth global and liver‐specific JCAD deficiency postponed liver regeneration after PH as indicated by reduced gene expression of cell cycle transition and DNA replication. Prolonged retention in G1 phase and failure to transition over the cell cycle checkpoint in JCAD‐KO cell line was indicated by a FUCCI live‐imaging system as well as pharmacologic blockage. JCAD replenishment by adenovirus reversed the impaired DNA synthesis in JCAD‐KO primary hepatocyte in exposure to EGF, which was abrogated by a Yes‐associated protein (YAP) inhibitor, verteporfin. Mechanistically, JCAD competed with large tumour suppressor 2 (LATS2) for WWC1 interaction, leading to LATS2 inhibition and thereafter YAP activation, and enhanced expression of cell cycle‐associated genes.ConclusionJCAD deficiency led to delayed regeneration after PH as a result of blockage in cell cycle progression through the Hippo–YAP signalling pathway. These findings uncovered novel functions of JCAD and suggested a potential strategy for improving graft growth and function post liver transplantation.Key Points JCAD deficiency leads to an impaired liver growth after PH due to cell division blockage. JCAD competes with LATS2 for WWC1 interaction, resulting in LATS2 inhibition, YAP activation and enhanced expression of cell cycle‐associated genes. Delineation of JCADHippoYAP signalling pathway would facilitate to improve prognosis of acute liver failure and graft growth in living‐donor liver transplantation.

show abstract

Aberrant hedgehog signaling is responsible for the highly invasive behavior of a subpopulation of hepatoma cells

Cited by 36 publications

References 40 publications

Hedgehog signaling pathway affects the sensitivity of hepatoma cells to drug therapy through the ABCC1 transporter

Hedgehog signaling pathway affects the sensitivity of hepatoma cells to drug therapy through the ABCC1 transporter

Genomic alterations of oligodendrogliomas at distant recurrence

JCAD deficiency delayed liver regenerative repair through the Hippo–YAP signalling pathway

Contact Info

Product

Resources

About