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Biomedicines
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Pathogenesis and Counteracting Strategies of Hepatocellular Carcinoma, Cholangiocarcinoma and Urothelial...
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Pathogenesis and Counteracting Strategies of Hepatocellular Carcinoma, Cholangiocarcinoma and Urothelial Carcinoma

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: closed (15 September 2023) | Viewed by 20578

Special Issue Editor

Prof. Dr. Kung-Hao Liang

E-Mail Website
Guest Editor
1. Department of Medical Research,Taipei Veterans General Hospital, Taipei 112, Taiwan
2. Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
3. Institute of Food Safety and Health Risk Assessment, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
Interests: Human Genome; Inherited diseases; hepatitis; Hepatocellular Carcinoma; Liver Cirrhosis; Pediatric brain tumors; Immunology; Transitional cell carcinoma; Cholangiocarcinoma; Lung cancer; Artificial Intelligence

Special Issue Information

Dear Colleagues,

Hepatocellular carcinoma, cholangiocarcinoma and urothelial carcinoma are aggressive cancers causing morbidity, mortality and health burden worldwide. Hepatocellular carcinoma is mostly caused by chronic viral infections, while the etiology of cholangiocarcinoma and urothelial carcinoma are only partly known so far. The pathogenesis of these cancers awaits more research in order to be fully elucidated. Novel therapeutic targets and treatment strategies may arise from the investigations of the pathogenic mechanisms. Immunotherapies are becoming more and more important in treating all cancers with the advancement of knowledge about tumor–immune system interactions. The stratification of patients with respect to their distinct pathogenic mechanisms and estimated outcomes are helpful for guiding personally optimized treatments. We hereby solicit academic manuscripts regarding pathogenesis and counteracting strategies for hepatocellular carcinoma, cholangiocarcinoma and urothelial carcinoma to be considered for publication in this Special Issue of Biomedicines.

The scope of this Special Issue includes but is not limited to:

  • Novel etiologies of hepatocellular carcinoma, cholangiocarcinoma and urothelial carcinoma;
  • Novel pathogenic mechanisms;
  • Novel biomarkers for effective patient stratification with distinct patient prognosis or treatment outcomes;
  • Novel therapeutic targets;
  • Novel therapeutic agents;
  • Novel treatment roadmaps and strategies.

Prof. Dr. Kung-Hao Liang
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • precision medicine
  • biosignature
  • cancer genomics
  • target therapy
  • tumor–immune system interactions

Published Papers (5 papers)

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Research

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17 pages, 2520 KiB  
Article
Simultaneous Inhibition of Mcl-1 and Bcl-2 Induces Synergistic Cell Death in Hepatocellular Carcinoma
by Marlen Michalski, Magdalena Bauer, Franziska Walz, Deniz Tümen, Philipp Heumann, Petra Stöckert, Manuela Gunckel, Claudia Kunst, Arne Kandulski, Stephan Schmid, Martina Müller and Karsten Gülow
Biomedicines 2023, 11(6), 1666; https://doi.org/10.3390/biomedicines11061666 - 08 Jun 2023
Cited by 2 | Viewed by 1341
Abstract
Despite the recent approval of new therapies, the prognosis for patients with hepatocellular carcinoma (HCC) remains poor. There is a clinical need for new highly effective therapeutic options. Here, we present a combined application of BH3-mimetics as a potential new treatment option for [...] Read more.
Despite the recent approval of new therapies, the prognosis for patients with hepatocellular carcinoma (HCC) remains poor. There is a clinical need for new highly effective therapeutic options. Here, we present a combined application of BH3-mimetics as a potential new treatment option for HCC. BH3-mimetics inhibit anti-apoptotic proteins of the BCL-2 family and, thus, trigger the intrinsic apoptosis pathway. Anti-apoptotic BCL-2 proteins such as Bcl-2 and Mcl-1 are frequently overexpressed in HCC. Therefore, we analyzed the efficacy of the two BH3-mimetics ABT-199 (Bcl-2 inhibitor) and MIK665 (Mcl-1 inhibitor) in HCC cell lines with differential expression levels of endogenous Bcl-2 and Mcl-1. While administration of one BH3-mimetic alone did not substantially trigger cell death, the combination of two inhibitors enhanced induction of the intrinsic apoptosis pathway. Both drugs acted synergistically, highlighting the effectivity of this specific BH3-mimetic combination, particularly in HCC cell lines. These results indicate the potential of combining inhibitors of the BCL-2 family as new therapeutic options in HCC. Full article
(This article belongs to the Special Issue Pathogenesis and Counteracting Strategies of Hepatocellular Carcinoma, Cholangiocarcinoma and Urothelial Carcinoma)
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12 pages, 1870 KiB  
Article
Oncogenic Roles of Polycomb Repressive Complex 2 in Bladder Cancer and Upper Tract Urothelial Carcinoma
by Eric Yi-Hsiu Huang, Yu-Kuang Chen, Chen-Pu Ou, Yi-Ting Chen, Sung-Fang Chen, William J. Huang and Kung-Hao Liang
Biomedicines 2022, 10(11), 2925; https://doi.org/10.3390/biomedicines10112925 - 14 Nov 2022
Viewed by 1751
Abstract
Cancers of the urinary tract are one of the most common malignancies worldwide, causing high morbidity and mortality, and representing a social burden. Upper tract urothelial carcinoma (UTUC) accounts for 5–10% of urinary tract cancers, and its oncogenic mechanisms remain elusive. We postulated [...] Read more.
Cancers of the urinary tract are one of the most common malignancies worldwide, causing high morbidity and mortality, and representing a social burden. Upper tract urothelial carcinoma (UTUC) accounts for 5–10% of urinary tract cancers, and its oncogenic mechanisms remain elusive. We postulated that cancers of the lower and the upper urinary tract may share some important oncogenic mechanisms. Therefore, the oncogenic mechanisms discovered in the lower urinary tract may guide the investigation of molecular mechanisms in the upper urinary tract. Based on this strategy, we revisited a high-quality transcriptome dataset of 510 patients with non-muscle invasive bladder cancer (NMIBC), and performed an innovative gene set enrichment analysis of the transcriptome. We discovered that the epigenetic regulation of polycomb repressive complex 2 (PRC2) is responsible for the recurrence and progression of lower-track urinary cancers. Additionally, a PRC2-related gene signature model was discovered to be effective in classifying bladder cancer patients with distinct susceptibility of subsequent recurrence and progression (log-rank p < 0.001 and = 0.001, respectively). We continued to discover that the same model can differentiate stage T3 UTUC patients from stage Ta/T1 patients (p = 0.026). Immunohistochemical staining revealed the presence of PRC2 components (EZH2, EED, and SUZ12) and methylated PRC2 substrates (H3K27me3) in the archived UTUC tissues. The H3K27me3 exhibited higher intensity and area intensity product in stage T3 UTUC tissues than in stage Ta/T1 tissues (p = 0.006 and 0.015, respectively), implicating stronger PRC2 activity in advanced UTUC. The relationship between H3K27 methylation and gene expression is examined using correlations. The H3K27me3 abundance is positively correlated with the expression levels of CDC26, RP11-2B6, MAPK1IP1L, SFR1, RP11-196B3, CDK5RAP2, ANXA5, STX11, PSMD5, and FGFRL1. It is also negatively correlated with CNPY2, KB-1208A12, RP11-175B9, ZNF692, RANP8, RP11-245C17, TMEM266, FBXW9, SUGT1P2, and PRH1. In conclusion, PRC2 and its epigenetic effects are major oncogenic mechanisms underlying both bladder cancer and UTUC. The epigenetically regulated genes of PRC2 in urothelial carcinoma were also elucidated using correlation statistics. Full article
(This article belongs to the Special Issue Pathogenesis and Counteracting Strategies of Hepatocellular Carcinoma, Cholangiocarcinoma and Urothelial Carcinoma)
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19 pages, 1823 KiB  
Article
SYNE1 Exonic Variant rs9479297 Contributes to Concurrent Hepatocellular and Transitional Cell Carcinoma Double Primary Cancer
by Yu-De Chu, Kwong-Ming Kee, Wey-Ran Lin, Ming-Wei Lai, Sheng-Nan Lu, Wen-Hung Chung, See-Tong Pang and Chau-Ting Yeh
Biomedicines 2021, 9(12), 1819; https://doi.org/10.3390/biomedicines9121819 - 02 Dec 2021
Cited by 3 | Viewed by 1887
Abstract
Unexpected high risk of synchronous/metachronous hepatocellular carcinoma (HCC) and transitional cell carcinoma (TCC) co-occurrence has been discovered previously. Here, we searched for genetic variation contributing to the co-occurrence of this double primary cancer (DPC). Using targeted exome sequencing, a panel of variants associated [...] Read more.
Unexpected high risk of synchronous/metachronous hepatocellular carcinoma (HCC) and transitional cell carcinoma (TCC) co-occurrence has been discovered previously. Here, we searched for genetic variation contributing to the co-occurrence of this double primary cancer (DPC). Using targeted exome sequencing, a panel of variants associated with concurrent DPC was identified. However, only a nonsynonymous variant within the Spectrin Repeat Containing Nuclear Envelope Protein 1 (SYNE1) gene was associated with DPC occurrence (p = 0.002), compared with that in the healthy population. Further independent cohort verification analysis revealed that the SYNE1-rs9479297-TT genotype (versus TC + CC genotypes) was enriched in patients with DPC, compared with that in those with TCC alone (p = 0.039), those with HCC alone (p = 0.006), those with non-HCC/non-TCC (p < 0.001), and healthy population (p < 0.001). SYNE1 mRNA expression reduced in both patients with HCC and TCC, and its lower expression in HCC was associated with shorter recurrence-free (p = 0.0314) and metastasis-free (p = 0.0479) survival. SYNE1-rs9479297 genotypes were correlated with tissue SYNE1 levels and clinical outcomes in HCC patients. Finally, SYNE1 silencing enhanced the cell proliferation and migration of HCC/TCC cells. In conclusion, SYNE1-rs9479297 genotypes were associated with HCC/TCC DPC co-occurrence and correlated with SYNE1 expression, which in turn contributed to HCC/TCC cell proliferation and migration, thereby affecting clinical outcomes. Full article
(This article belongs to the Special Issue Pathogenesis and Counteracting Strategies of Hepatocellular Carcinoma, Cholangiocarcinoma and Urothelial Carcinoma)
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Review

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40 pages, 3061 KiB  
Review
Pathogenesis and Current Treatment Strategies of Hepatocellular Carcinoma
by Deniz Tümen, Philipp Heumann, Karsten Gülow, Cagla-Nur Demirci, Lidia-Sabina Cosma, Martina Müller and Arne Kandulski
Biomedicines 2022, 10(12), 3202; https://doi.org/10.3390/biomedicines10123202 - 09 Dec 2022
Cited by 26 | Viewed by 9282
Abstract
Hepatocellular carcinoma (HCC) is the most frequent liver cancer with high lethality and low five-year survival rates leading to a substantial worldwide burden for healthcare systems. HCC initiation and progression are favored by different etiological risk factors including hepatitis B virus (HBV) and [...] Read more.
Hepatocellular carcinoma (HCC) is the most frequent liver cancer with high lethality and low five-year survival rates leading to a substantial worldwide burden for healthcare systems. HCC initiation and progression are favored by different etiological risk factors including hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, non-/and alcoholic fatty liver disease (N/AFLD), and tobacco smoking. In molecular pathogenesis, endogenous alteration in genetics (TP53, TERT, CTNNB1, etc.), epigenetics (DNA-methylation, miRNA, lncRNA, etc.), and dysregulation of key signaling pathways (Wnt/β-catenin, JAK/STAT, etc.) strongly contribute to the development of HCC. The multitude and complexity of different pathomechanisms also reflect the difficulties in tailored medical therapy of HCC. Treatment options for HCC are strictly dependent on tumor staging and liver function, which are structured by the updated Barcelona Clinic Liver Cancer classification system. Surgical resection, local ablative techniques, and liver transplantation are valid and curative therapeutic options for early tumor stages. For multifocal and metastatic diseases, systemic therapy is recommended. While Sorafenib had been the standalone HCC first-line therapy for decades, recent developments had led to the approval of new treatment options as first-line as well as second-line treatment. Anti-PD-L1 directed combination therapies either with anti-VEGF directed agents or with anti-CTLA-4 active substances have been implemented as the new treatment standard in the first-line setting. However, data from clinical trials indicate different responses on specific therapeutic regimens depending on the underlying pathogenesis of hepatocellular cancer. Therefore, histopathological examinations have been re-emphasized by current international clinical guidelines in addition to the standardized radiological diagnosis using contrast-enhanced cross-sectional imaging. In this review, we emphasize the current knowledge on molecular pathogenesis of hepatocellular carcinoma. On this occasion, the treatment sequences for early and advanced tumor stages according to the recently updated Barcelona Clinic Liver Cancer classification system and the current algorithm of systemic therapy (first-, second-, and third-line treatment) are summarized. Furthermore, we discuss novel precautional and pre-therapeutic approaches including therapeutic vaccination, adoptive cell transfer, locoregional therapy enhancement, and non-coding RNA-based therapy as promising treatment options. These novel treatments may prolong overall survival rates in regard with quality of life and liver function as mainstay of HCC therapy. Full article
(This article belongs to the Special Issue Pathogenesis and Counteracting Strategies of Hepatocellular Carcinoma, Cholangiocarcinoma and Urothelial Carcinoma)
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17 pages, 679 KiB  
Review
Effects of Thyroid Hormones on Lipid Metabolism Pathologies in Non-Alcoholic Fatty Liver Disease
by Chia-Jung Liao, Po-Shuan Huang, Hui-Tzu Chien, Tzu-Kang Lin, Chau-Ting Yeh and Kwang-Huei Lin
Biomedicines 2022, 10(6), 1232; https://doi.org/10.3390/biomedicines10061232 - 25 May 2022
Cited by 5 | Viewed by 5432
Abstract
The typical modern lifestyle contributes to the development of many metabolic-related disorders, as exemplified by metabolic syndrome. How to prevent, resolve, or avoid subsequent deterioration of metabolic disturbances and the development of more serious diseases has become an important and much-discussed health issue. [...] Read more.
The typical modern lifestyle contributes to the development of many metabolic-related disorders, as exemplified by metabolic syndrome. How to prevent, resolve, or avoid subsequent deterioration of metabolic disturbances and the development of more serious diseases has become an important and much-discussed health issue. Thus, the question of the physiological and pathological roles of thyroid hormones (THs) in metabolism has never gone out of fashion. Although THs influence almost all organs, the liver is one of the most important targets as well as the hub of metabolic homeostasis. When this homeostasis is out of balance, diseases may result. In the current review, we summarize the common features and actions of THs, first focusing on their effects on lipid metabolism in the liver. In the second half of the review, we turn to a consideration of non-alcoholic fatty liver disease (NAFLD), a disease characterized by excessive accumulation of fat in the liver that is independent of heavy alcohol consumption. NAFLD is a growing health problem that currently affects ~25% of the world’s population. Unfortunately, there are currently no approved therapies specific for NAFLD, which, if left uncontrolled, may progress to more serious diseases, such as cirrhosis or liver cancer. This absence of effective treatment can also result in the development of non-alcoholic steatohepatitis (NASH), an aggressive form of NAFLD that is the leading cause of liver transplantation in the United States. Because THs play a clear role in hepatic fat metabolism, their potential application in the prevention and treatment of NAFLD has attracted considerable research attention. Studies that have investigated the use of TH-related compounds in the management of NAFLD are also summarized in the latter part of this review. An important take-home point of this review is that a comprehensive understanding of the physiological and pathological roles of THs in liver fat metabolism is possible, despite the complexities of this regulatory axis—an understanding that has clinical value for the specific management of NAFLD. Full article
(This article belongs to the Special Issue Pathogenesis and Counteracting Strategies of Hepatocellular Carcinoma, Cholangiocarcinoma and Urothelial Carcinoma)
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