scholarly journals YAP and TAZ Heterogeneity in Primary Liver Cancer: An Analysis of Its Prognostic and Diagnostic Role

2019 ◽  
Vol 20 (3) ◽  
pp. 638 ◽  
Author(s):  
Matthias Van Haele ◽  
Iván Moya ◽  
Ruçhan Karaman ◽  
Guy Rens ◽  
Janne Snoeck ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Liver Tumors ◽  
Primary Liver Cancer ◽  
Hippo Pathway ◽  
Disease Free Survival ◽  
Decisive Role ◽  
Binding Motif ◽  
Keratin 19 ◽  
Liver Cancers

Primary liver cancer comprises a diverse group of liver tumors. The heterogeneity of these tumors is seen as one of the obstacles to finding an effective therapy. The Hippo pathway, with its downstream transcriptional co-activator Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), has a decisive role in the carcinogenesis of primary liver cancer. Therefore, we examined the expression pattern of YAP and TAZ in 141 patients with hepatocellular carcinoma keratin 19 positive (HCC K19+), hepatocellular carcinoma keratin 19 negative (HCC K19−), combined hepatocellular–cholangiocarcinoma carcinoma (cHCC-CCA), or cholangiocarcinoma (CCA). All cHCC-CCA and CCA patients showed high expression levels for YAP and TAZ, while only some patients of the HCC group were positive. Notably, we found that a histoscore of both markers is useful in the challenging diagnosis of cHCC-CCA. In addition, positivity for YAP and TAZ was observed in the hepatocellular and cholangiocellular components of cHCC-CCA, which suggests a single cell origin in cHCC-CCA. Within the K19− HCC group, our results demonstrate that the expression of YAP is a statistically significant predictor of poor prognosis when observed in the cytoplasm. Nuclear expression of TAZ is an even more specific and independent predictor of poor disease-free survival and overall survival of K19− HCC patients. Our results thus identify different levels of YAP/TAZ expression in various liver cancers that can be used for diagnostics.

scholarly journals Hepatic Hippo signaling inhibits development of hepatocellular carcinoma

2020 ◽  
Vol 26 (4) ◽  
pp. 742-750
Author(s):  
Yuchen Liu ◽  
Xiaohui Wang ◽  
Yingzi Yang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Primary Liver Cancer ◽  
Hippo Pathway ◽  
Hepatocyte Proliferation ◽  
Binding Motif ◽  
Hippo Signaling ◽  
Human Liver Cancer ◽  
Kinase Cascade ◽  
The Hippo Pathway

Primary liver cancer is one of the most common cancer worldwide. Hepatocellular carcinoma (HCC) in particular, is the second leading cause of cancer deaths in the world. The Hippo signaling pathway has emerged as a major oncosuppressive pathway that plays critical roles inhibiting hepatocyte proliferation, survival, and HCC formation. A key component of the Hippo pathway is the inhibition of yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) transcription factors by the Hippo kinase cascade. Aberrant activation of YAP or TAZ has been found in several human cancers including HCC. It is also well established that YAP/TAZ activation in hepatocytes causes HCC in mouse models, indicating that YAP/TAZ are potential therapeutic targets for human liver cancer. In this review, we summarize the recent findings regarding the multifarious roles of Hippo/YAP/TAZ in HCC development, and focus on their cell autonomous roles in controlling hepatocyte proliferation, differentiation, survival and metabolism as well as their non-cell autonomous in shaping the tumor microenvironment.

TP53 R249G/S mutation as an independent prognosis indicator in hepatocellular carcinoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16622-e16622
Author(s):  
Ledu Zhou ◽  
Ying Xu ◽  
Dong Wang ◽  
Ke Ye ◽  
Liang Xiao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Point Mutation ◽  
Primary Liver Cancer ◽  
Gene Mutations ◽  
Disease Free Survival ◽  
Primary Hepatocellular Carcinoma ◽  
Rank Test ◽  
High Morbidity ◽  
Tissue Samples

e16622 Background: Many cancers could be driven by some specially mutations exampled as EGFR in lung cancer, influenced prognosis prominently. However, there were few related studies in liver cancer, although primary liver cancer was a common malignant tumor causing high morbidity and mortality. Methods: 97 patients diagnosed with primary hepatocellular carcinoma were enrolled in this study. Operative tissue samples were collected and analyzed using hybridization capture based NGS ERSeq method from all patients. Results: 1088 somatic mutations were identified in tissue samples. Targeted-capture sequencing of 1,021 genes that are frequently mutated in solid tumors revealed that the most frequently mutated genes were TP53 (59%), TERT (32%) and AXIN1 (19%). By using the least absolute shrinkage and selection operator (LASSO), the recurrence risks were constructed on the basis of five-gene mutations, AXIN1, CTNNB1, LRP1B, PDGFRA and TP53. The ROC curve was 0.813 and 0.882 in training and validation cohorts, respectively. TP53 R249G/S point mutation was predicted prognostic independently. Up to 60% TP53 R249S mutated patients occurred recurrence, while less than 30% TP53 R249 wildtype patients occurred recurrence ( P = 0.0002). Patients with R249G/S point mutation showed a worse prognosis. The median disease-free survival time was 8.0 VS 45.0 months in R249G/S mutated group (n = 79) and R249- wildtype (n = 18) group, respectively (Log-rank test, P = 0.0364). Conclusions: In various cancer types, TP53 has a broad-spectrum mutation, but only in hepatocellular carcinoma, TP53 mutations are highly concentrated at the R249 point, which was considered to be related to aflatoxin infection, and mutations at this site can significantly affect the prognosis of patients. The discovery of this target also provide clue for subsequent targeted treatment of liver cancer.

scholarly journals Deregulation of the Histone Lysine-Specific Demethylase 1 Is Involved in Human Hepatocellular Carcinoma

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 810 ◽  
Author(s):  
Sangchul Kim ◽  
Amina Bolatkan ◽  
Syuzo Kaneko ◽  
Noriko Ikawa ◽  
Ken Asada ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Therapeutic Target ◽  
Primary Liver Cancer ◽  
Disease Free Survival ◽  
Immunohistochemical Analysis ◽  
Rank Test ◽  
Positive Staining ◽  
Histone Lysine ◽  
Lysine Specific Demethylase

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Given that the standard-of-care for advanced liver cancer is limited, there is an urgent need to develop a novel molecular targeted therapy to improve therapeutic outcomes for HCC. In order to tackle this issue, we conducted functional analysis of the histone lysine-specific demethylase (LSD1) to explore the possibility that this enzyme acts as a therapeutic target in HCC. According to immunohistochemical analysis, 232 of 303 (77%) HCC cases showed positive staining of LSD1 protein, and its expression was correlated with several clinicopathological characteristics, such as female gender, AFP (alpha-fetoprotein) levels, and HCV (hepatitis C virus) infectious. The survival curves for HCC using the Kaplan–Meier method and the log-rank test indicate that positive LSD1 protein expression was significantly associated with decreased rates of overall survival (OS) and disease-free survival (DFS); the multivariate analysis indicates that LSD1 expression was an independent prognostic factor for both OS and DFS in patients with HCC. In addition, knockout of LSD1 using the CRISPR/Cas9 system showed a significantly lower number of colony formation units (CFUs) and growth rate in both SNU-423 and SNU-475 HCC cell lines compared to the corresponding control cells. Moreover, LSD1 knockout decreased cells in S phase of SNU-423 and SNU-475 cells with increased levels of H3K4me1/2 and H3K9me1/2. Finally, we identified the signaling pathways regulated by LSD1 in HCC, including the retinoic acid (RA) pathway. Our findings imply that deregulation of LSD1 can be involved in HCC; further studies may explore the usefulness of LSD1 as a therapeutic target of HCC.

scholarly journals Treatment of Combined Hepatocellular and Cholangiocarcinoma

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 794 ◽  
Author(s):  
Simona Leoni ◽  
Vito Sansone ◽  
Stefania De Lorenzo ◽  
Luca Ielasi ◽  
Francesco Tovoli ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Unmet Needs ◽  
Primary Liver Cancer ◽  
Therapeutic Options ◽  
Neoplastic Cells ◽  
Dual Nature ◽  
Risk Of Recurrence ◽  
Combined Hepatocellular And Cholangiocarcinoma ◽  
Liver Cancers

Combined hepatocellular and cholangiocarcinoma (HCC-CC) is a rare primary liver cancer. It is constituted by neoplastic cells of both hepatocellular and cholangiocellular derivation. Different histology types of HCC-CC have been reported, hinting at heterogeneous carcinogenic pathways leading to the development of this cancer. Due to its rarity and complexity, mixed HCC-CC is a scantly investigated condition with unmet needs and unsatisfactory outcomes. Surgery remains the preferred treatment in resectable patients. The risk of recurrence, however, is high, especially in comparison with other primary liver cancers such as hepatocellular carcinoma. In unresectable or recurring patients, the therapeutic options are challenging due to the dual nature of the neoplastic cells. Consequently, the odds of survival of patients with HCC-CC remains poor. We analysed the literature systematically about the treatment of mixed HCC-CC, reviewing the main therapeutic options and their outcomes and analysing the most interesting developments in this topic with a focus on new potential therapeutic avenues.

scholarly journals The TACE’s role in the management of primary liver cancer

2019 ◽  
Vol 3 (Issue 4) ◽  
pp. 250
Author(s):  
Andrei Seregin ◽  
Egor Zagainov ◽  
Pavel Ryhtik ◽  
Angelina Chichkanova ◽  
Lubov Shkalova ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Ultrasound Guidance ◽  
Liver Tumors ◽  
Primary Liver Cancer ◽  
Locally Advanced ◽  
Underlying Disease ◽  
Artery Pseudoaneurysm ◽  
Advanced Tumor ◽  
Tumor Lesion

Objective:  Identify the most effective and safe method of transcatheter hepatic artery chemoembolization (TACE) in patients with primary liver cancer. Methods:  Overall, 139 patients, who underwent 558 TACE procedures were included in the study. Gender in the group of patients was distributed approximately equally and amounted to 72 men (52%) and 67 women (48%), the average age was 57.8 (9.9) years (range from 23 to 92 years). In most patients, the underlying disease for the development of hepatocellular carcinoma was cirrhosis of the liver in the outcome of hepatitis C or B. Characteristics of liver tumors were examined by magnetic resonance imaging or computed tomography and ultrasound. For verification of the diagnosis, a percutaneous liver biopsy was performed under ultrasound guidance, and the level of alpha-fetoprotein was also determined. All patients were considered unresectable due to cirrhosis and / or local spread of the tumor. Chemoembolization was performed by following scheme: one procedure in 2 months, not less than 3 procedures.  Doxorubicin was used for chemotherapy. As a carrier of chemotherapy, Lipiodol (Guerbet, France) or saturable Hepaspheres (Merit Medical, USA) were used. Each patient received from 3 to 13 procedures.  Results: Postembolization syndrome occurred in all cases, but was effectively treated. One patient died due to acute liver failure with the borderline stage of the disease according to the BCLC classification (EASL 2012) and the multinodular form of HCC. There were no serious complications in the treatment process. In two patients in the area of the puncture of the femoral artery, pseudoaneurysm was formed, which was eliminated by compression under ultrasound guidance. About 10% of patients developed subacute cholecystitis in the postoperative period and were associated with non-targeted chemoembolization in the cystic artery. In all patients, the symptoms of cholecystitis at the time of discharge were relieved  conservatively. Survival median – 19 months. Dynamics of tumors was assessed by RECIST criteria. In the group of patients with hepatocellular carcinoma after first 3 TAСEs partial response and stabilization were observed in 83%, progression in 17%. In 18 cases (13%), histologically proved tumor necrosis after TAСE was achieved, without progression during follow-up.  Three patients after reducing of tumor size was resected, 32 patients continue treatment. Conclusion: Transcatheter arterial chemoembolization in the treatment of hepatocellular carcinoma shows high efficacy, low mortality and the development of postoperative complications in patients with concomitant liver cirrhosis and locally advanced tumor lesion.

scholarly journals Mitochondrial Dynamics and Liver Cancer

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2571
Author(s):  
María Isabel Hernández-Alvarez ◽  
Antonio Zorzano
Keyword(s):  
Liver Cancer ◽  
Liver Tumors ◽  
Mitochondrial Dynamics ◽  
Primary Liver Cancer ◽  
Mitochondrial Morphology ◽  
Mitochondrial Dynamic ◽  
Mitochondrial Homeostasis ◽  
Liver Cancers ◽  
Rising Incidence ◽  
Novel Therapeutic Strategies

Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer. Due to its rising incidence and limited therapeutic options, HCC has become a leading cause of cancer-related death worldwide, accounting for 85% of all deaths due to primary liver cancers. Standard therapy for advanced-stage HCC is based on anti-angiogenic drugs such as sorafenib and, more recently, lenvatinib and regorafenib as a second line of treatment. The identification of novel therapeutic strategies is urgently required. Mitochondrial dynamics describes a group of processes that includes the movement of mitochondria along the cytoskeleton, the regulation of mitochondrial morphology and distribution, and connectivity mediated by tethering and fusion/fission events. In recent years, mitochondrial dynamic processes have emerged as key processes in the maintenance of liver mitochondrial homeostasis. In addition, some data are accumulating on the role played by mitochondrial dynamics during cancer development, and specifically on how such dynamics act directly on tumor cells or indirectly on cells responsible for tumor aggression and defense. Here, we review the data that suggest mitochondrial dynamics to be involved in the development of liver tumors.

scholarly journals Development of Alpha-emitting radioembolization for Hepatocellular Carcinoma: Longitudinal Monitoring of Actinium-225’s Daughters Through SPECT Imaging

2020 ◽  
Author(s):  
Yong Du ◽  
Angel Cortez ◽  
Mohammadreza Zarisfi ◽  
Anders Josefsson ◽  
Rebecca Krimins ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Mouse Model ◽  
Normal Tissue ◽  
Liver Tumors ◽  
Primary Liver Cancer ◽  
Treatment Options ◽  
Spect Imaging ◽  
Hepatic Tumors

Abstract Hepatocellular carcinoma is the most common primary liver cancer and the fifth most frequently diagnosed cancer worldwide. Most patients with advanced disease are offered non-surgical palliative treatment options. This work explores the first α-emitting radioembolization for the treatment and monitoring of hepatic tumors. Furthermore, this works demonstrates the first in vivo simultaneous multiple-radionuclide SPECT images of the complex decay chain of an [225Ac]Ac-labeled agent using a clinical SPECT system to monitor the temporal distribution. Methods: A DOTA chelator was modified with a lipophilic moiety and radiolabeled with Actinium-225. The resulting agent, [225Ac]Ac-DOTA-TDA, was emulsified in Lipiodol® and evaluated in vivo in mouse model and the VX2 rabbit technical model of liver cancer. SPECT imaging was performed to monitor distribution of the TAT agent and the free daughters.Results: [225Ac]Ac-DOTA-TDA was shown to retain within the HEP2G tumors and VX2 tumor, with minimal uptake within normal tissue. In the mouse model, significant improvements in overall survival were observed. SPECT imaging was able to distinguish between the Actinium-225 agent (Francium-221) and the loss of the longer lived daughter, Bismuth-213. Conclusion: A TAT agent emulsified in Lipiodol® is capable of targeting liver tumors with minimal accumulation in normal tissue, providing a potential therapeutic agent for the treatment of HCC as well as a variety of hepatic tumors. In addition, SPECT imaging presented here provides a foundation for imaging methodology and protocols that can be rapidly translated into the clinic to monitor Actinium-225-labeled agents.

scholarly journals Effects Which M6A RNA Methylation Regulation Exerts on the Prognosis of Hepatocellular Carcinoma

2020 ◽  
Author(s):  
Baoxue Jia ◽  
Xiaojian Pei ◽  
Yue Sun ◽  
Yaming Xing ◽  
Jinna Hu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Human Cancer ◽  
Primary Liver Cancer ◽  
Lasso Regression ◽  
Rna Methylation ◽  
Normal Tissues ◽  
Liver Cancers ◽  
M6a Rna Methylation ◽  
The Relationship

Abstract Background: Hepatocellular carcinoma (HCC) ,which has been known as the most common subtype in the range of primary liver cancer . Besides, it hails as one of China ’s common cancers , giving rise to the major cancer death cause in men. N6 methyladenosine (m6A) RNA methylation is under the regulation of m6A RNA methylation regulators in dynamic way (the proteins of "writer" "eraser"; "reader"). More and more evidences show that the m6A modification level is connected with self-renewal of tumor stem cells, the growth, proliferation, anti chemotherapy and radiosensitivity of tumor cells. The relationship between m6A RNA and human cancer types has been confirmed in a variety of cancers. This research aims to investigate the relationship betwixt m6A RNA methylation regulators and liver cancer. Methods: firstly, the comparison of the expression levels harbored by 13 major m6A RNA methylation regulators in liver cancer with normal tissues was conducted by means of the data of TCGA database. Secondly, we cluster the presentation data of m6A RNA methylated regulator uniformly and dissect HCC tissue into two subgroups (group 1 and 2) by comparing these subgroups according to the overall survival rate (OS), WHO phase and pathological level . Thirdly, based on the combination of least absolute contraction with selection operator (lasso) regression, the risk characteristics of m6A RNA methylation regulators was constructed , which affected OS in TCGA analysis. Results: there were significant differences in the presentation degrades held by 12 major m6A RNA methylation regulators in liver cancers and normal tissues. The primary liver cancer was divided into 1 and 2 groups. It was found that the OS of 1 subgroup was poor, the WHO stage was high and the pathological grade was high. In TCGA analysis, five m6A methylation regulators (YTHDF1, ZC3H13, YTHDF2, METTL3 and KIAA1429) were selected to affect OS, and a risk marker significantly related to who staging was constructed, which was also an independent prognostic marker of OS. Conclusion: m6A RNA methylation regulator is a key player in the progression of HCC and has potential value in the prediction and treatment of HCC.

An Overview of Natural Plant Products in the Treatment of Hepatocellular Carcinoma

2019 ◽  
Vol 18 (13) ◽  
pp. 1838-1859 ◽  
Author(s):  
Divya Rawat ◽  
Somi Shrivastava ◽  
Rayees A. Naik ◽  
Saurabh K. Chhonker ◽  
Aditi Mehrotra ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Primary Liver Cancer ◽  
Herbal Medicines ◽  
Incidence Rates ◽  
Chronic Liver ◽  
Chronic Infections ◽  
Natural Plant ◽  
Plant Products ◽  
Liver Cancers

Background: Liver cancer is the fifth most commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide. Among the liver cancers, hepatocellular carcinoma has been reported to be responsible for 85-90% of primary liver cancer and it is the second most common cause of cancer mortality with 700,000 deaths documented annually. The major risk factors of HCC include chronic infections with the hepatitis B (HBV) or hepatitis C (HCV) virus, chronic liver diseases, alcoholism as well as dietary carcinogens, such as aflatoxins. Highest incidence rates are estimated to occur in Asia and Africa. Objective: The effectiveness of current man-made agents in treating chronic liver disease is not satisfactory and they have uninvited side effects. Herbal medicines are extensively used all over the world; however, there is still a vast gap in their acceptance by the scientific community. Plants are rich in secondary metabolites and phytochemicals obtained from both, dietary and non-dietary sources. Natural plant products are potent therapeutic as well as chemopreventive agents for numerous chronic diseases like cardiovascular, metabolic, neurodegenerative and neoplastic diseases. Results: Dietary phytochemicals such as curcumin, resveratrol, quercetin, silibinin, N-trans-feruloyl octopamine, lycopene, emodin, caffeine, urolithin A and Phloretin have been found to be useful for the treatment of HCC and other diseases. According to recent reports 60% of the anticancer medication in current use has been obtained from natural sources. Conclusion: Thus, derivatives from plants have played an essential role in cancer prevention due to their pleiotropic abilities to scavenge free radicals, inhibit cell growth and induce apoptosis.

Genomics and Interventional Oncology in Primary Liver Cancer

2020 ◽  
Vol 04 (01) ◽  
pp. 053-059
Author(s):  
Ryan Slovak ◽  
Meaghan Dendy Case ◽  
Hyun S. Kim
Keyword(s):  
Hepatocellular Carcinoma ◽  
Personalized Medicine ◽  
Liver Cancer ◽  
Precision Medicine ◽  
Intrahepatic Cholangiocarcinoma ◽  
Interventional Oncology ◽  
Primary Liver Cancer ◽  
Concise Overview ◽  
Liver Cancers

AbstractPersonalized medicine is revolutionizing oncologic care. Molecular and imaging “fingerprinting” of cancer through genomics, radiomics, and radiogenomics has allowed for the meticulous characterization of many forms of malignancy, including primary liver cancers. With this data, treatments are being developed that precisely target and exploit key variations in individual tumors. As these methods continue to evolve, interventional oncologists are well positioned to capitalize on the advances being made. This article will provide a concise overview of the genomic, radiomic, and radiogenomic research on hepatocellular carcinoma and intrahepatic cholangiocarcinoma, in addition to discussions on how precision medicine would relate to interventional oncology.

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