scholarly journals Hedgehog Signaling, a Critical Pathway Governing the Development and Progression of Hepatocellular Carcinoma

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 123
Author(s):  
Jia Ding ◽  
Hui-Yan Li ◽  
Li Zhang ◽  
Yuan Zhou ◽  
Jian Wu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Hedgehog Signaling ◽  
Target Genes ◽  
Relevant Literature ◽  
Hepatoma Cells ◽  
Signaling Molecules ◽  
Molecular Profile ◽  
Critical Pathway ◽  
Hh Signaling

Hedgehog (Hh) signaling is a classic morphogen in controlling embryonic development and tissue repairing. Aberrant activation of Hh signaling has been well documented in liver cancer, including hepatoblastoma, hepatocellular carcinoma (HCC) and cholangiocarcinoma. The present review aims to update the current understanding on how abnormal Hh signaling molecules modulate initiation, progression, drug resistance and metastasis of HCC. The latest relevant literature was reviewed with our recent findings to provide an overview regarding the molecular interplay and clinical relevance of the Hh signaling in HCC management. Hh signaling molecules are involved in the transformation of pre-carcinogenic lesions to malignant features in chronic liver injury, such as nonalcoholic steatohepatitis. Activation of GLI target genes, such as ABCC1 and TAP1, is responsible for drug resistance in hepatoma cells, with a CD133−/EpCAM− surface molecular profile, and GLI1 and truncated GLI1 account for the metastatic feature of the hepatoma cells, with upregulation of matrix metalloproteinases. A novel bioassay for the Sonic Hh ligand in tissue specimens may assist HCC diagnosis with negative α-fetoprotein and predict early microvascular invasion. In-depth exploration of the Hh signaling deepens our understanding of its molecular modulation in HCC initiation, drug sensitivity and metastasis, and guides precise management of HCC on an individual basis.

scholarly journals Hedgehog Signaling Pathway and Autophagy in Cancer

2018 ◽  
Vol 19 (8) ◽  
pp. 2279 ◽  
Author(s):  
Xian Zeng ◽  
Dianwen Ju
Keyword(s):  
Drug Resistance ◽  
Hedgehog Signaling ◽  
Biological Process ◽  
Cellular Component ◽  
Hedgehog Signaling Pathway ◽  
Drug Resistant ◽  
Multiple Cancers ◽  
Success Stories ◽  
Cancer Types ◽  
Hh Signaling

Hedgehog (Hh) pathway controls complex developmental processes in vertebrates. Abnormal activation of Hh pathway is responsible for tumorigenesis and maintenance of multiple cancers, and thus addressing this represents promising therapeutic opportunities. In recent years, two Hh inhibitors have been approved for basal cell carcinoma (BCC) treatment and show extraordinary clinical outcomes. Meanwhile, a series of novel agents are being developed for the treatment of several cancers, including lung cancer, leukemia, and pancreatic cancer. Unfortunately, Hh inhibition fails to show satisfactory benefits in these cancer types compared with the success stories in BCC, highlighting the need for better understanding of Hh signaling in cancer. Autophagy, a conserved biological process for cellular component elimination, plays critical roles in the initiation, progression, and drug resistance of cancer, and therefore, implied potential to be targeted. Recent evidence demonstrated that Hh signaling interplays with autophagy in multiple cancers. Importantly, modulating this crosstalk exhibited noteworthy capability to sensitize primary and drug-resistant cancer cells to Hh inhibitors, representing an emerging opportunity to reboot the efficacy of Hh inhibition in those insensitive tumors, and to tackle drug resistance challenges. This review will highlight recent advances of Hh pathway and autophagy in cancers, and focus on their crosstalk and the implied therapeutic opportunities.

scholarly journals The role of the Hedgehog signaling pathway in cancer: A comprehensive review

2018 ◽  
Vol 18 (1) ◽  
pp. 8-20 ◽  
Author(s):  
Ana Marija Skoda ◽  
Dora Simovic ◽  
Valentina Karin ◽  
Vedran Kardum ◽  
Semir Vranic ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Signaling Pathway ◽  
Hedgehog Signaling ◽  
Target Genes ◽  
Biological Effects ◽  
Signal Transmission ◽  
Adenosine Monophosphate ◽  
Evolutionary Pathway ◽  
Gli Transcription Factors ◽  
Hh Signaling

The Hedgehog (Hh) signaling pathway was first identified in the common fruit fly. It is a highly conserved evolutionary pathway of signal transmission from the cell membrane to the nucleus. The Hh signaling pathway plays an important role in the embryonic development. It exerts its biological effects through a signaling cascade that culminates in a change of balance between activator and repressor forms of glioma-associated oncogene (Gli) transcription factors. The components of the Hh signaling pathway involved in the signaling transfer to the Gli transcription factors include Hedgehog ligands (Sonic Hh [SHh], Indian Hh [IHh], and Desert Hh [DHh]), Patched receptor (Ptch1, Ptch2), Smoothened receptor (Smo), Suppressor of fused homolog (Sufu), kinesin protein Kif7, protein kinase A (PKA), and cyclic adenosine monophosphate (cAMP). The activator form of Gli travels to the nucleus and stimulates the transcription of the target genes by binding to their promoters. The main target genes of the Hh signaling pathway are PTCH1, PTCH2, and GLI1. Deregulation of the Hh signaling pathway is associated with developmental anomalies and cancer, including Gorlin syndrome, and sporadic cancers, such as basal cell carcinoma, medulloblastoma, pancreatic, breast, colon, ovarian, and small-cell lung carcinomas. The aberrant activation of the Hh signaling pathway is caused by mutations in the related genes (ligand-independent signaling) or by the excessive expression of the Hh signaling molecules (ligand-dependent signaling – autocrine or paracrine). Several Hh signaling pathway inhibitors, such as vismodegib and sonidegib, have been developed for cancer treatment. These drugs are regarded as promising cancer therapies, especially for patients with refractory/advanced cancers.

scholarly journals Regulation of Hedgehog Signaling by miRNAs and Nanoformulations: A Possible Therapeutic Solution for Colorectal Cancer

2021 ◽  
Vol 10 ◽  
Author(s):  
Zeeshan Javed ◽  
Muhammad Javed Iqbal ◽  
Amna Rasheed ◽  
Haleema Sadia ◽  
Shahid Raza ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Small Molecules ◽  
Hedgehog Signaling ◽  
Target Genes ◽  
Therapeutic Option ◽  
High Specificity ◽  
Alternative Drug ◽  
Delivery Platform ◽  
Hh Signaling ◽  
Differentiation And Proliferation

Hedgehog (Hh) signaling aberrations trigger differentiation and proliferation in colorectal cancer (CRC). However, the current approaches which inhibit this vital cellular pathway provoke some side effects. Therefore, it is necessary to look for new therapeutic options. MicroRNAs are small molecules that modulate expression of the target genes and can be utilized as a potential therapeutic option for CRC. On the other hand, nanoformulations have been implemented in the treatment of plethora of diseases. Owing to their excessive bioavailability, limited cytotoxicity and high specificity, nanoparticles may be considered as an alternative drug delivery platform for the Hh signaling mediated CRC. This article reviews the Hh signaling and its involvement in CRC with focus on miRNAs, nanoformulations as potential diagnostic/prognostic and therapeutics for CRC.

scholarly journals Hedgehog Signaling and Truncated GLI1 in Cancer

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2114 ◽  
Author(s):  
Daniel Doheny ◽  
Sara G. Manore ◽  
Grace L. Wong ◽  
Hui-Wen Lo
Keyword(s):  
Hedgehog Signaling ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Human Cancers ◽  
Cell Growth And Differentiation ◽  
Hh Signaling ◽  
Patched 1 ◽  
Truncated Variants

The hedgehog (HH) signaling pathway regulates normal cell growth and differentiation. As a consequence of improper control, aberrant HH signaling results in tumorigenesis and supports aggressive phenotypes of human cancers, such as neoplastic transformation, tumor progression, metastasis, and drug resistance. Canonical activation of HH signaling occurs through binding of HH ligands to the transmembrane receptor Patched 1 (PTCH1), which derepresses the transmembrane G protein-coupled receptor Smoothened (SMO). Consequently, the glioma-associated oncogene homolog 1 (GLI1) zinc-finger transcription factors, the terminal effectors of the HH pathway, are released from suppressor of fused (SUFU)-mediated cytoplasmic sequestration, permitting nuclear translocation and activation of target genes. Aberrant activation of this pathway has been implicated in several cancer types, including medulloblastoma, rhabdomyosarcoma, basal cell carcinoma, glioblastoma, and cancers of lung, colon, stomach, pancreas, ovarian, and breast. Therefore, several components of the HH pathway are under investigation for targeted cancer therapy, particularly GLI1 and SMO. GLI1 transcripts are reported to undergo alternative splicing to produce truncated variants: loss-of-function GLI1ΔN and gain-of-function truncated GLI1 (tGLI1). This review covers the biochemical steps necessary for propagation of the HH activating signal and the involvement of aberrant HH signaling in human cancers, with a highlight on the tumor-specific gain-of-function tGLI1 isoform.

scholarly journals An absolute requirement for Cubitus interruptus in Hedgehog signaling

Development ◽  
2001 ◽  
Vol 128 (5) ◽  
pp. 733-742 ◽  
Author(s):  
N. Methot ◽  
K. Basler
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Hedgehog Signaling ◽  
Target Gene ◽  
Target Genes ◽  
Signal Transduction Pathway ◽  
Transduction Pathway ◽  
Cubitus Interruptus ◽  
Target Gene Expression ◽  
Hh Signaling

Hedgehog (Hh) proteins play diverse organizing roles in animal development by regulating gene expression in responding cells. Several components of the Hh signal transduction pathway have been identified, yet their precise role in mediating the various outputs of the pathway is still poorly understood. The Gli homolog Cubitus interruptus (Ci) is involved in controlling the transcription of Drosophila Hh target genes and thus represents the most downstream component known in this pathway. We address the question of whether the Hh pathway is distally branched or, in other words, whether the regulation of Ci activity is the sole output of Hh signaling. Putative Ci-independent branches of Hh signaling are explored by analyzing the behavior of cells that lack Ci but have undergone maximal activation of the Hh transduction pathway due to the removal of Patched (Ptc). The analysis of target gene expression and morphogenetic read-outs of Hh in embryonic, larval and adult stages indicates that Ci is absolutely required for all examined aspects of Hh outputs. We interpret this as evidence against the existence of Ci-independent branches in the Hh signal transduction pathway and propose that most cases of apparent Ci/Gli-independent Hh output can be attributed to the derepression of target gene expression in the absence of Ci/Gli repressor function.

scholarly journals The Notch Target Genes Hey1 and Hes7 Transcriptionally Suppress Gli1 Expression and Hedgehog Signaling in Hodgkin-Reed/Sternberg Cells of Classical Hodgkin Lymphoma: A Novel Mechanism of Drug Resistance

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 275-275
Author(s):  
Rolf Schwarzer ◽  
Julia Godau ◽  
Hermann Einsele ◽  
Franziska Jundt
Keyword(s):  
Drug Resistance ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Hodgkin Lymphoma ◽  
Target Genes ◽  
Classical Hodgkin Lymphoma ◽  
Notch Inhibition ◽  
Hh Signaling

Abstract Tumor cell proliferation and survival of Hodgkin/Reed-Sternberg (HRS) cells are triggered through Jagged1 ligand-induced Notch1 signaling via homotypic and heterotypic cell-cell interactions in classical Hodgkin lymphoma. The developmental pathway Notch partly mediates its effects in HRS cells by stimulation of alternative NF-kB signaling. We further demonstrated that high-level expression of the essential Notch coactivator Mastermind-like 2 and downregulation of the Notch inhibitor Deltex1 contribute to aberrant activation of Notch signaling in HRS cells. Our data suggested that targeting the Notch pathway is a rational treatment strategy in classical Hodgkin lymphoma. In this study we analyzed Notch inhibition by use of the gamma secretase inhibitor GSI XII in a Hodgkin lymphoma xenotransplantation model. To this end the HRS cell line L540cy (1 x 107 cells/per mouse) was transplanted into NOD/SCID mice. After tumor growth (0.3 cm³ mean tumor volume) mice were treated daily with increasing doses of GSI XII (5-10 mg/kg). Surprisingly, L540cy cells were completely drug-resistant in vivo in contrast to high GSI XII sensitivity in vitro. To dissect potential mechanisms of drug resistance we performed human StellARrayTM quantitative polymerase chain reaction (qPCR) arrays to analyze Notch target genes in GSI XII-treated compared to untreated L540cy cells. Interestingly, inhibition of Notch activity resulted in strong mRNA upregulation of the transcription factor glioma-associated oncogene 1 (Gli1), a final effector of the developmental signaling pathway Hedgehog (HH). Chromatin immunoprecipitation (ChIP) further revealed that both negative regulatory Notch target proteins Hey1 and Hes7 directly bind three different N-boxes present in the GLI1 first intron to suppress GLI1 mRNA expression in untreated L540cy cells. In general, the HH pathway is activated through ligand binding of secreted Sonic Hedgehog (SHH). As a result Gli transcription factors translocate to the nucleus and induce target gene expression such as GLI1 or CCND1. Despite high secretion of SHH by HRS cells after two days in culture (conditioned medium), HH signaling was inactive in untreated L540cy cells. Only after release of the negative regulatory Notch targets of the hairy and enhancer of split (HES) family through Notch inhibition and concomitant increase of Gli1 expression, HH signaling was activated by SHH. HH signaling mediated drug resistance of L540cy cells in conditioned medium compared to fresh medium (SHH negative) and thereby compensated for reduced Notch activity in vitro. We hypothesized that this mechanism might contribute to GSI XII drug resistance in vivo. To proof our hypothesis we coinhibited the Notch and HH pathways in L540cy cells. As expected inhibition of the HH pathway alone by use of cyclopamine did not significantly reduce growth of L540cy cells. However, simultaneous targeting of L540cy tumors through GSI XII and cyclopamine efficiently controlled tumor cell growth. Our data indicate a first molecular link between Notch and HH in HRS cells mediating drug resistance. We suggest inhibition of both developmental pathways for effective HRS tumor growth control. Disclosures No relevant conflicts of interest to declare.

scholarly journals Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1715
Author(s):  
Macus Hao-Ran Bao ◽  
Carmen Chak-Lui Wong
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Liver Cancer ◽  
Effective Treatment ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Metabolic Reprogramming ◽  
Combination Therapies ◽  
Low Oxygen ◽  
Treatment Regimens

Hypoxia, low oxygen (O2) level, is a hallmark of solid cancers, especially hepatocellular carcinoma (HCC), one of the most common and fatal cancers worldwide. Hypoxia contributes to drug resistance in cancer through various molecular mechanisms. In this review, we particularly focus on the roles of hypoxia-inducible factor (HIF)-mediated metabolic reprogramming in drug resistance in HCC. Combination therapies targeting hypoxia-induced metabolic enzymes to overcome drug resistance will also be summarized. Acquisition of drug resistance is the major cause of unsatisfactory clinical outcomes of existing HCC treatments. Extra efforts to identify novel mechanisms to combat refractory hypoxic HCC are warranted for the development of more effective treatment regimens for HCC patients.

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