Small-molecule-mediated reprogramming: a silver lining for regenerative medicine DOI Creative Commons
Yohan Kim, Jaemin Jeong, Dongho Choi

et al.

Experimental & Molecular Medicine, Journal Year: 2020, Volume and Issue: 52(2), P. 213 - 226

Published: Feb. 1, 2020

Abstract Techniques for reprogramming somatic cells create new opportunities drug screening, disease modeling, artificial organ development, and cell therapy. The development of techniques has grown exponentially since the discovery induced pluripotent stem (iPSCs) by transduction four factors ( OCT3/4 , SOX2 c-MYC KLF4 ) in mouse embryonic fibroblasts. Initial studies on iPSCs led to direct-conversion using transcription expressed mainly target cells. However, with a virus risks integrating viral DNA can be complicated oncogenes. To address these problems, many researchers are developing methods that use clinically applicable small molecules growth factors. This review summarizes research trends factors, including their modes action.

Language: Английский

Canonical Wnt signaling promotes HSC glycolysis and liver fibrosis through an LDH-A/HIF-1α transcriptional complex DOI Creative Commons

Feixia Wang,

Li Chen, Desong Kong

et al.

Hepatology, Journal Year: 2023, Volume and Issue: 79(3), P. 606 - 623

Published: Sept. 21, 2023

Background and Aims: Aerobic glycolysis reprogramming occurs during HSC activation, but how it is initiated sustained remains unknown. We investigated the mechanisms by which canonical Wnt signaling regulated therapeutic implication for liver fibrosis. Approach Results: Glycolysis was examined in HSC-LX2 cells upon manipulation of Wnt/β-catenin signaling. Nuclear translocation lactate dehydrogenase A (LDH-A) its interaction with hypoxia-inducible factor-1α (HIF-1α) were using molecular simulation site-directed mutation assays. The pharmacological relevance discoveries intensified primary cultures, rodent models, human samples. enhanced Wnt3a reduced β-catenin inhibitor or small interfering RNA (siRNA). Wnt3a-induced rapid transactivation high expression LDH-A dependent on TCF4. also stimulated nuclear through importin β2 interplay a noncanonical location signal LDH-A. Mechanically, bound to HIF-1α stability obstructing hydroxylation-mediated proteasome degradation, leading increased glycolytic genes. Gly28 residue identified be responsible formation LDH-A/HIF-1α transcription complex stabilization HIF-1α. Furthermore, LDH-A-mediated required activation presence Wnt3a. Results vivo showed that fibrosis alleviated HSC-specific knockdown mice. XAV-939 mitigated fibrosis, abrogated overexpression mice Conclusions: Inhibition targeting had promise

Language: Английский

Citations

44
Metabolic reprogramming in the tumor microenvironment of liver cancer DOI Creative Commons
Jian Lin, Dongning Rao, Mao Zhang

et al.

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: Jan. 31, 2024

The liver is essential for metabolic homeostasis. onset of cancer often accompanied by dysregulated function, leading to rearrangements. Overwhelming evidence has illustrated that cellular metabolism can, in turn, promote anabolic growth and tumor propagation a hostile microenvironment. In addition supporting continuous survival, disrupted process also creates obstacles the anticancer immune response restrains durable clinical remission following immunotherapy. this review, we elucidate communication between cells their surrounding discuss how reprogramming impacts microenvironment efficacy We describe crucial role gut-liver axis remodeling crosstalk surveillance escape, highlighting novel therapeutic opportunities.

Language: Английский

Citations

44
Pharmacogenomic profiling of intra-tumor heterogeneity using a large organoid biobank of liver cancer DOI Creative Commons
Hui Yang,

Jinghui Cheng,

Hao Zhuang

et al.

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(4), P. 535 - 551.e8

Published: April 1, 2024

Inter- and intra-tumor heterogeneity is a major hurdle in primary liver cancer (PLC) precision therapy. Here, we establish PLC biobank, consisting of 399 tumor organoids derived from 144 patients, which recapitulates histopathology genomic landscape parental tumors, reliable for drug sensitivity screening, as evidenced by both vivo models patient response. Integrative analysis dissects heterogeneity, regarding genomic/transcriptomic characteristics to seven clinically relevant drugs, well clinical associations. Pharmacogenomic identifies validates multi-gene expression signatures predicting response better stratification. Furthermore, reveal c-Jun mediator lenvatinib resistance through JNK β-catenin signaling. A compound (PKUF-01) comprising moieties veratramine (c-Jun inhibitor) synthesized screened, exhibiting marked synergistic effect. Together, our study characterizes the develops predictive biomarker panels, lenvatinib-resistant mechanism combination

Language: Английский

Citations

37
A spatiotemporal atlas of mouse liver homeostasis and regeneration DOI
Jiangshan Xu, Pengcheng Guo, Shijie Hao

et al.

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(5), P. 953 - 969

Published: April 16, 2024

Language: Английский

Citations

17
Hepatocellular carcinoma: signaling pathways and therapeutic advances DOI Creative Commons

Jiaojiao Zheng,

Siying Wang, Lei Xia

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Feb. 6, 2025

Abstract Liver cancer represents a major global health concern, with projections indicating that the number of new cases could surpass 1 million annually by 2025. Hepatocellular carcinoma (HCC) constitutes around 90% liver and is primarily linked to factors incluidng aflatoxin, hepatitis B (HBV) C (HCV), metabolic disorders. There are no obvious symptoms in early stage HCC, which often leads delays diagnosis. Therefore, HCC patients usually present tumors advanced incurable stages. Several signaling pathways dis-regulated cause uncontrolled cell propagation, metastasis, recurrence HCC. Beyond frequently altered therapeutically targeted receptor tyrosine kinase (RTK) involved differentiation, telomere regulation, epigenetic modification stress response also provide therapeutic potential. Investigating key their inhibitors pivotal for achieving advancements management At present, primary approaches (TKI), immune checkpoint (ICI), combination regimens. New trials investigating therapies involving ICIs TKIs or anti-VEGF (endothelial growth factor) therapies, as well combinations two immunotherapy The outcomes these expected revolutionize across all Here, we here comprehensive review cellular pathways, potential, evidence derived from late-stage clinical discuss concepts underlying earlier trials, biomarker identification, development more effective therapeutics

Language: Английский

Citations

7
Emerging regulatory mechanisms and functions of biomolecular condensates: implications for therapeutic targets DOI Creative Commons
Soyoung Jeon, Yong‐Duck Chung, Jae‐Sung Lim

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Jan. 6, 2025

Cells orchestrate their processes through complex interactions, precisely organizing biomolecules in space and time. Recent discoveries have highlighted the crucial role of biomolecular condensates-membrane-less assemblies formed condensation proteins, nucleic acids, other molecules-in driving efficient dynamic cellular processes. These condensates are integral to various physiological functions, such as gene expression intracellular signal transduction, enabling rapid finely tuned responses. Their ability regulate signaling pathways is particularly significant, it requires a careful balance between flexibility precision. Disruption this can lead pathological conditions, including neurodegenerative diseases, cancer, viral infections. Consequently, emerged promising therapeutic targets, with potential offer novel approaches disease treatment. In review, we present recent insights into regulatory mechanisms by which influence pathways, roles health disease, strategies for modulating condensate dynamics approach. Understanding these emerging principles may provide valuable directions developing effective treatments targeting aberrant behavior diseases.

Language: Английский

Citations

3
Wnt/β-Catenin Signaling in Liver Cancers DOI Open Access
Wenhui Wang, Ron Smits, Haiping Hao

et al.

Cancers, Journal Year: 2019, Volume and Issue: 11(7), P. 926 - 926

Published: July 2, 2019

Liver cancer is among the leading global healthcare issues associated with high morbidity and mortality. consists of hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), hepatoblastoma (HB), several other rare tumors. Progression has been witnessed in understanding interactions between etiological as well environmental factors host development liver cancers. However, pathogenesis remains poorly understood, hampering design rational strategies aiding preventing Accumulating evidence demonstrates that aberrant activation Wnt/β-catenin signaling pathway plays an important role initiation progression HCC, CCA, HB. Targeting potentiates a novel avenue for treatment, which may benefit from numerous small-molecule inhibitors biologic agents this field. In review, we discuss interaction various components early precancerous lesion acquired mechanisms to further enhance promote robust formation at later stages. Additionally, shed light on current relevant tested cancers provide future perspectives preclinical clinical studies.

Language: Английский

Citations

130
Signaling pathways in hepatocellular carcinoma DOI
Teresa García‐Lezana, Juan L López-Cánovas, Augusto Villanueva

et al.

Advances in cancer research, Journal Year: 2020, Volume and Issue: unknown, P. 63 - 101

Published: Nov. 24, 2020

Language: Английский

Citations

111
Pathogenesis of Cholangiocarcinoma DOI Open Access
Pedro M. Rodrigues, Paula Olaizola,

Nuno A. Paiva

et al.

Annual Review of Pathology Mechanisms of Disease, Journal Year: 2020, Volume and Issue: 16(1), P. 433 - 463

Published: Dec. 3, 2020

Cholangiocarcinoma (CCA) encompasses a group of malignancies that can arise at any point in the biliary tree. Although considered rare cancer, incidence CCA is increasing globally. The silent and asymptomatic nature these tumors, particularly their early stages, combination with high aggressiveness, intra- intertumor heterogeneity, chemoresistance, significantly compromises efficacy current therapeutic options, contributing to dismal prognosis. During last few years, efforts have been made unveil etiologies pathogenesis tumors develop more effective therapies. In this review, we summarize findings field CCA, mainly focusing on mechanisms pathogenesis, cells origin, genomic epigenetic abnormalities, molecular alterations,

Language: Английский

Citations

108
Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications DOI Creative Commons
Juan Carrillo-Reixach, Laura Torrens,

Marina Simon‐Coma

et al.

Journal of Hepatology, Journal Year: 2020, Volume and Issue: 73(2), P. 328 - 341

Published: March 30, 2020

Hepatoblastoma (HB) is a rare disease. Nevertheless, it the predominant pediatric liver cancer, with limited therapeutic options for patients aggressive tumors. Herein, we aimed to uncover mechanisms of HB pathobiology and identify new biomarkers targets in move towards precision medicine advanced HB.We performed comprehensive genomic, transcriptomic epigenomic characterization 159 clinically annotated samples from 113 HB, using high-throughput technologies.We discovered widespread epigenetic footprint that includes hyperediting tumor suppressor BLCAP concomitant genome-wide dysregulation RNA editing overexpression mainly non-coding genes oncogenic 14q32 DLK1-DIO3 locus. By unsupervised analysis, identified 2 clusters (Epi-CA, Epi-CB) distinct degrees DNA hypomethylation CpG island hypermethylation are associated C1/C2/C2B subtypes. Based on these findings, defined first molecular risk stratification (MRS-HB), which encompasses 3 main prognostic categories improves current clinical approach. The MRS-3 category (28%), by strong locus expression Epi-CB methylation features, was characterized CTNNB1 NFE2L2 mutations, progenitor-like phenotype aggressiveness. Finally, choline kinase alpha as promising target intermediate high-risk HBs, its inhibition cell lines patient-derived xenografts strongly abrogated growth.These findings provide detailed insight into features could be used improve approaches develop treatments HB.Hepatoblastoma childhood cancer has been understudied. We have cutting-edge technologies expand our knowledge this cancer. Our biological can management pave way development novel therapies

Language: Английский

Citations

107