Identification of the β-catenin/JNK/prothymosin-alpha axis as a novel target of sorafenib in hepatocellular carcinoma cells

Lin, Yi-Te; Chao, Chuck C.‐K.

doi:10.18632/oncotarget.5738

Cited by 20 publications

(14 citation statements)

References 57 publications

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“…Around 40-70% HCCs showed aberrant expression of nuclear β-catenin, thereby accentuating Wnt/β-catenin signaling activity (25)(26)(27)(28). Key mutations are involved in this process (29)(30)(31).…”

Section: Discussionmentioning

confidence: 99%

Expression and Prognostic Significance of CDK8 and β-Catenin in Hepatocellular Carcinoma

Lim¹

2020

In Vivo

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Background/Aim: Cyclin-dependent kinase 8 (CDK8) is known to play an important role in the early development and progression of various cancers, and the Wnt/β-catenin pathway is also involved in cancer progression. Nevertheless, relatively little is known about the regulatory mechanisms of the β-catenin pathway in hepatocellular carcinoma (HCC). Materials and Methods: The complete clinicopathological features of 122 pairs of HCC and adjacent non-tumor tissues were analyzed and immunohistochemistry was used to detect the aberrant expression of CDK8 and βcatenin. Overall survival rates (OSRs) were evaluated using the Kaplan-Meier method and Cox multivariate analysis was used to assess the prognostic values. Results: Aberrant expression of nuclear β-catenin and CDK8 are independent prognostic variables that negatively affect the OSR. The aberrant expression of CDK8 was associated with the dysregulated expression of β-catenin and correlated with a poor prognosis. Conclusion: Inhibition of CDK8 and/or nuclear β-catenin expression pattern could serve as a promising therapeutic strategy for the treatment of HCC.Cyclin-dependent kinase 8 (CDK8), a member of CDK family of proteins, is a ubiquitously expressed transcription regulating serine/threonine kinase. CDK8 is located on chromosome 13 and has been implicated in transcriptional regulation of various cancers such as melanoma, colorectal, breast, prostate, and pancreatic cancer (1-5). The activation of CDK8 is essential for β-catenin-dependent transcription and oncogenesis (6, 7). Philip et al. (4) reported an important role for CDK8 in gene-specific transcription either through its association with the mediator complex or by phosphorylation of transcription factors. These properties laid the foundation for the discovery of CDK8 inhibitors and for attempts to develop strategies for CDK8-targeted cancer therapies. The Wnt/β-catenin, estrogen receptor-responsive genes, and drosophila mothers against decapentaplegic are CDK8-modulated transcriptional signaling pathways that have been implicated in the regulation of oncogenesis in various cancers (1,4,5,8,9). β-catenin was originally reported as a membrane adhesion protein of the cadherin-mediated cell-cell adhesion system. It is the pivotal nuclear effector in the Wnt signal cascade (10). In the absence of Wnt signaling, β-catenin localizes to the cell membrane and functions in E-cadherin-mediated cell-cell adhesion. Aberrant degradation of β-catenin results in an increase of cytoplasmic β-catenin and leads to its nuclear translocation. Nuclear β-catenin is significantly associated with the invasion and metastasis of various human cancers such as carcinomas of the esophagus, stomach, colon, and melanomas (11,12).The suppression of CDK8 with a small-interfering RNA (siRNA) or short-hairpin RNA (shRNA) was shown to inhibit the proliferation of cancer cells of the colon, prostate, and breast based on preclinical data (1,3,5). Moreover, CDK8-mediated phosphorylation inhibits the cytotoxic activity of natural killer (NK) cells...

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Section: Discussionmentioning

confidence: 99%

Expression and Prognostic Significance of CDK8 and β-Catenin in Hepatocellular Carcinoma

Lim¹

2020

In Vivo

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“…Around 40–70% of HCCs show β-catenin nuclear accumulation, augmenting Wnt/β-catenin signaling activity [74,75,76,77]. Mutations in key genes are involved in this process [78,79,80].…”

Section: Liver Cancersmentioning

confidence: 99%

Wnt/β-Catenin Signaling in Liver Cancers

Wang

Smits

Hao

et al. 2019

Cancers

124

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

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“…Mitf participates in a feed-back loop regulatory mechanism with β-catenin (19) and may alter its transcriptional activity (5). Additionally, Igf2bp1 and Ptma are direct targets in the β-catenin pathway (20,21). Moreover, Igf2bp1 post-transcriptionally regulates Mitf and Myc, whose transcription is in turn controlled by βcatenin (22).…”

Section: Discussionmentioning

confidence: 99%

Potential Prognostic Molecular Signatures in a Preclinical Model of Melanoma

Fortis

Anastasopoulou

Voutsas

et al. 2017

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Numerous studies have revealed a variety of pathways involved in the development of melanoma, however, the molecular and genetic divergence of underlying mechanisms remain vague. In a mouse model, we studied the expression pattern of insulin-like growth factor 2 mRNAbinding protein 1 (Igf2bp1) and target genes microphthalmiaassociated transcription factor (Mitf), v-myc avian myelocytomatosis viral oncogene homolog (Myc), B-cell lymphoma 2 (Bcl2), prothymosin alpha (Ptma) and melan-A (Mlana) in relation to tumor-growth characteristics. The in vivo expression of the aforementioned genes was assessed by quantitative Real Time-Polymerase Chain Reaction (RT-PCR) in tumors established by B16-F1-derived clones. Gene expression was correlated with tumor growth characteristics. Simultaneous expression of elevated levels of Myc, Igf2bp1, Ptma and Mitf characterizes tumors with a more aggressive phenotype. Our findings introduce a tumor-specific molecular signature possibly associated with melanoma heterogeneity. The concomitant overexpression of key molecules such as IGF2BP1, PTMA, MYC and MITF could serve as prognostic or predictive marker.Melanoma is a very heterogenic cancer with great in vivo plasticity (1). Although the diversity of melanomas is known, the underlying molecular and genetic differences remain obscure (2). Thus, identifying intra-tumoral molecular signatures might introduce novel biomarkers of prognostic significance. A number of studies have unveiled a variety of molecules and several distinct pathways involved in the onset of melanoma. Some focused on the multifaceted and complicated role of wingless-related integration site (Wnt)/βcatenin pathway (3, 4). However, other studies have also pinpointed microphthalmia-associated transcription factor (MITF) and insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) as drivers in melanoma initiation and progression.MITF is a major transcription factor, dynamically transcribed by β-catenin complexes (5), active in normal melanocytes and malignant melanoma cells (6). Its deregulated expression has been described as a causal event in melanomas, resulting from gene amplification (7), as well as, from the ectopic expression of the RNA binding protein IGF2BP1 (8). As an RNA-binding protein, IGF2BP1 exerts its mode of action via regulating the intracellular levels of its targets. Among them, besides MITF, there are many notorious oncogenes such as v-myc avian myelocytomatosis viral oncogene homolog (MYC), glioma-associated oncogene family zinc finger 1 (GLI1), insulin-like growth factor 2 (IGF2), Kirsten rat sarcoma viral oncogene homolog (KRAS), multidrug resistance protein 1 (MDR-1), beta-transducin repeat containing E3 ubiquitin protein ligase pseudogene 1 (BTRCP1) and homing cell adhesion molecule (CD44) (9). It has been reported that overexpression of IGF2BP1 results in upregulation of one or more of these target genes, depending on the specific type of tissue (10). Although its expression is absent or scarce in normal adult tissues, it is detected in al...

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Identification of the β-catenin/JNK/prothymosin-alpha axis as a novel target of sorafenib in hepatocellular carcinoma cells

Cited by 20 publications

References 57 publications

Expression and Prognostic Significance of CDK8 and β-Catenin in Hepatocellular Carcinoma

Expression and Prognostic Significance of CDK8 and β-Catenin in Hepatocellular Carcinoma

Wnt/β-Catenin Signaling in Liver Cancers

Potential Prognostic Molecular Signatures in a Preclinical Model of Melanoma

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