scholarly journals The distinct responsiveness of cytokeratin 19-positive hepatocellular carcinoma to regorafenib

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Jianyong Zhuo ◽  
Di Lu ◽  
Zuyuan Lin ◽  
Xinyu Yang ◽  
Modan Yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Transplantation ◽  
Mitochondrial Respiration ◽  
Therapeutic Option ◽  
Cytokeratin 19 ◽  
Tumor Control ◽  
Therapeutic Effects ◽  
Potential Marker ◽  
Pdx Models ◽  
Hcc Cells

AbstractCytokeratin 19-positive (CK19+) hepatocellular carcinoma (HCC) is an aggressive subtype characterized by early recurrence and chemotherapy tolerance. However, there is no specific therapeutic option for CK19+ HCC. The correlation between tumor recurrence and expression status of CK19 were studied in 206 patients undergoing liver transplantation for HCC. CK19−/+ HCC cells were isolated to screen effective antitumor drugs. The therapeutic effects of regorafenib were evaluated in patient-derived xenograft (PDX) models from 10 HCC patients. The mechanism of regorafenib on CK19+ HCC was investigated. CK19 positiveness indicated aggressiveness of tumor and higher recurrence risk of HCC after liver transplantation. The isolated CK19+ HCC cells had more aggressive behaviors than CK19− cells. Regorafenib preferentially increased the growth inhibition and apoptosis of CK19+ cells in vitro, whereas sorafenib, apatinib, and 5-fluorouracil did not. In PDX models from CK19−/+ HCC patients, the tumor control rate of regorafenib achieved 80% for CK19+ HCCs, whereas 0% for CK19− HCCs. RNA-sequencing revealed that CK19+ cells had elevated expression of mitochondrial ribosomal proteins, which are essential for mitochondrial function. Further experiments confirmed that regorafenib attenuated the mitochondrial respiratory capacity in CK19+ cells. However, the mitochondrial respiration in CK19− cells were faint and hardly repressed by regorafenib. The mitochondrial respiration was regulated by the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which was inhibited by regorafenib in CK19+ cells. Hence, CK19 could be a potential marker of the therapeutic benefit of regorafenib, which facilitates the individualized therapy for HCC. STAT3/mitochondria axis determines the distinct response of CK19+ cells to regorafenib treatment.

scholarly journals Hypoxic hepatocellular carcinoma cells acquire arsenic trioxide resistance through upregulating HIF-1α expression

2020 ◽  
Author(s):  
Yaoting Chen ◽  
Huiqing Li ◽  
Dong Chen ◽  
Xiongying Jiang ◽  
Weidong Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Protein Expression ◽  
Arsenic Trioxide ◽  
Therapeutic Effects ◽  
Advanced Hepatocellular Carcinoma ◽  
Antitumor Effects ◽  
P Glycoprotein ◽  
Hcc Cells

Abstract Background : Although arsenic trioxide (ATO) is used in the treatment of advanced hepatocellular carcinoma (HCC) in clinical trials, it is not satisfactory in terms of improving HCC patients’ overall survival. Intratumoral hypoxia and overexpression of hypoxia-inducible-1α (HIF-1α) may result in ATO-resistance and tumor progression. We investigated the mechanisms involving HIF-1α expression and acquired ATO chemoresistance in HCC cells and mice. Methods: The therapeutic effects of ATO in normoxic and hypoxic HCC cells were assessed using cell viability and apoptosis assays in vitro and a xenograft model in vivo . mRNA and protein expression of HIF-1α, P-glycoprotein, and VEGF were measured by qRT-PCR and western blotting. HIF-1α inhibition was performed to investigate the mechanism of ATO-resistance. VEGF secretion was tested using ELISA and tube-formation assays. Results : Compared to normoxic cells, hypoxic HCC cells were more resistant to ATO, with higher IC 50 values and less apoptosis, and upregulated HIF-1α protein expression, accompanied with the enhancement of P-glycoprotein and VEGF synthesis after ATO treatment. VEGF secretion was elevated in the supernatant of ATO-treated HCC cells, and this change can potentiate angiogenesis in vitro . HIF-1α inhibition attenuated ATO-resistance and angiogenesis, and promoted the anticancer effects of ATO both in vitro and in vivo by downregulating therapy-induced P-glycoprotein and VEGF overexpression. Conclusions : Hypoxic HCC cells acquire ATO resistance by upregulating HIF-1α levels; thus, combining ATO with a HIF-1α-targeting agent may lead to enhanced antitumor effects in HCC.

scholarly journals Does Risk-Adapted Proton Beam Therapy Have a Role as a Complementary or Alternative Therapeutic Option for Hepatocellular Carcinoma?

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 230 ◽  
Author(s):  
Tae Kim ◽  
Joong-Won Park ◽  
Bo Kim ◽  
Hyunjung Kim ◽  
Sung Moon ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Proton Beam ◽  
Therapeutic Option ◽  
Cancer Control ◽  
Proton Beam Therapy ◽  
Target Volume ◽  
Dose Fractionation ◽  
Tumor Control ◽  
Grade 3

To evaluate the role of risk-adapted proton beam therapy (PBT) in hepatocellular carcinoma (HCC) patients, a total of 243 HCC patients receiving risk-adapted PBT with three dose-fractionation regimens (regimen A [n = 40], B [n = 60], and C [n = 143]) according to the proximity of their gastrointestinal organs (<1 cm, 1–1.9 cm, and ≥2 cm, respectively) were reviewed: The prescribed doses to planning target volume 1 (PTV1) were 50 gray equivalents (GyE) (EQD2 [equivalent dose in 2 Gy fractions], 62.5 GyE10), 60 GyE (EQD2, 80 GyE10), and 66 GyE (EQD2, 91.3 GyE10) in 10 fractions, respectively, and those of PTV2 were 30 GyE (EQD2, 32.5 GyE10) in 10 fractions. In all patients, the five-year local recurrence-free survival (LRFS) and overall survival (OS) rates were 87.5% and 48.1%, respectively, with grade ≥3 toxicity of 0.4%. In regimens A, B, and C, the five-year LRFS and OS rates were 54.6%, 94.7%, and 92.4% (p < 0.001), and 16.7%, 39.2%, and 67.9% (p < 0.001), respectively. The five-year OS rates of the patients with the Modified Union for International Cancer Control (mUICC) stages I, II, III, and IVA and Barcelona Clinic Liver Cancer (BCLC) stages A, B, and C were 69.2%, 65.4%, 43.8%, and 26.6% (p < 0.001), respectively, and 65.1%, 40%, and 32.2% (p < 0.001), respectively. PBT could achieve promising long-term tumor control and have a potential role as a complementary or alternative therapeutic option across all stages of HCC.

Three-Dimensional Macroporous Sponge for the Culture of Hepatocellular Carcinoma Patient-Derived Xenograft Organoids

2021 ◽  
pp. 247263032110006
Author(s):  
Tan Boon Toh ◽  
Zheng Liu ◽  
Hanry Yu ◽  
Eliza Li Shan Fong
Keyword(s):  
Hepatocellular Carcinoma ◽  
Three Dimensional ◽  
Epithelial Cancer ◽  
Molecular Features ◽  
Patient Derived Xenograft ◽  
Carcinoma Patient ◽  
Cancer Types ◽  
Pdx Models ◽  
Hcc Cells

This protocol focuses on the culture of cells harvested from hepatocellular carcinoma (HCC) patient-derived xenografts (PDXs) as organoids using a cellulosic macroporous sponge scaffold. Compared with many other epithelial cancer types, the viability of HCC cells directly derived from patients or PDX models is notoriously challenging to maintain in vitro. We previously developed a macroporous sponge scaffold uniquely designed to provide biochemical and mechanical cues that support the culture of normal hepatocytes as spheroids with maintained functionality. Leveraging our success using this sponge scaffold to maintain normal hepatocytes in vitro, we recently demonstrated that a similar sponge scaffold enables the maintenance of HCC PDX cells as organoids with preserved viability, molecular features, and heterogeneity.

scholarly journals Blockade of AMPK-Mediated cAMP–PKA–CREB/ATF1 Signaling Synergizes with Aspirin to Inhibit Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1738
Author(s):  
Hongying Zhang ◽  
Songpeng Yang ◽  
Jiao Wang ◽  
Yangfu Jiang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Therapeutic Effects ◽  
Carbamoyl Phosphate ◽  
Cycle Enzyme ◽  
Phosphatase 2A ◽  
Hcc Cells

Aspirin can prevent or inhibit inflammation-related cancers, such as colorectal cancer and hepatocellular carcinoma (HCC). However, the effectiveness of chemotherapy may be compromised by activating oncogenic pathways in cancer cells. Elucidation of such chemoresistance mechanisms is crucial to developing novel strategies to maximize the anti-cancer effects of aspirin. Here, we report that aspirin markedly induces CREB/ATF1 phosphorylation in HCC cells, which compromises aspirin’s anti-HCC effect. Inhibition of AMP-activated protein kinase (AMPK) abrogates the induction of CREB/ATF1 phosphorylation by aspirin. Mechanistically, activation of AMPK by aspirin results in decreased expression of the urea cycle enzyme carbamoyl-phosphate synthase 1 (CPS1) in HCC cells and xenografts. Treatment with aspirin or CPS1 knockdown stimulates soluble adenylyl cyclase expression, thereby increasing cyclic AMP (cAMP) synthesis and stimulating PKA–CREB/ATF1 signaling. Importantly, abrogation of aspirin-induced CREB/ATF1 phosphorylation could sensitize HCC to aspirin. The bis-benzylisoquinoline alkaloid berbamine suppresses the expression of cancerous inhibitor of protein phosphatase 2A (CIP2A), leading to protein phosphatase 2A-mediated downregulation of CREB/ATF1 phosphorylation. The combination of berbamine and aspirin significantly inhibits HCC in vitro and in vivo. These data demonstrate that the regulation of cAMP-PKA-CREB/ATF1 signaling represents a noncanonical function of CPS1. Targeting the PKA–CREB/ATF1 axis may be a strategy to improve the therapeutic effects of aspirin on HCC.

scholarly journals Glutathione S-transferase A2 (GSTA2) Promotes Hepatocellular Carcinoma Recurrence After Liver Transplantation Through Modulating Reactive Oxygen Species Metabolism

2020 ◽  
Author(s):  
Kevin Tak-Pan NG ◽  
Oscar Wai-Ho Yeung ◽  
Yin Fan Lam ◽  
Jiang Liu ◽  
Hui Liu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Reactive Oxygen Species ◽  
Liver Transplantation ◽  
Early Phase ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Glutathione S Transferase ◽  
Proliferation And Metastasis ◽  
Hcc Recurrence ◽  
Hcc Cells

Abstract BackgroundAn inevitable hepatic injury at the early phase after liver transplantation vitally affects the late phase hepatocellular carcinoma (HCC) recurrence. However, their linkage and underlying risk factors of HCC recurrence are unclear. This study aimed to clarify the clinical impact and functional roles of glutathione S-transferase A2 (GSTA2) in affecting HCC recurrence after liver transplantation.MethodsExpression significance and prognostic value of hepatic and circulating GSTA2 in HCC recipients were examined. The polymorphism of GSTA2 transcript was analysed by Sanger sequencing. The functions and molecular mechanisms of GSTA2 in the proliferation and metastasis of HCC were characterized by molecular, cellular and animal experiments. ResultsThe GSTA2 expression was significantly correlated with the early phase hepatic and systemic injury and reactive oxygen species (ROS) level after liver transplantation. Importantly, the level of the early phase circulating GSTA2 protein was a significant predictor of HCC recurrence and survival of HCC recipients. Heterogeneous single nucleotide polymorphism at G335C of GSTA2 was significantly associated with poor survival of HCC recipients. The GSTA2 expression was positively correlated with the aggressiveness of HCCs. Overexpression of GSTA2, by endogenous or exogenous approaches, could enhance the proliferation and invasion of HCCs through activating epithelial-mesenchymal-transition promoting proteins. Targeted inhibition of GSTA2 remarkably suppressed the proliferation and metastasis of HCCs. Increased level of GSTA2 could compensate the H2O2-induced ROS stress and therefore protect the HCC cells from damage. Alteration of GSTA2 expression in HCC cells could influence the activation of ROS-associated JNK and AKT signaling pathways and the expression of ROS-associated genes in responding to the H2O2 condition. ConclusionsOur research discovered GSTA2 to be the significant risk factor of HCC recurrence via providing a favorable ROS environment for HCC to survival and progress. This study presents a novel functional biomarker for combating HCC recurrence after liver transplantation.

scholarly journals MiR-942-3p Promotes the Proliferation and Invasion of Hepatocellular Carcinoma Cells by Targeting MBL2

2019 ◽  
Vol 26 (1) ◽  
pp. 107327481984659 ◽  
Author(s):  
Chun-Yang Xu ◽  
Jun-Feng Dong ◽  
Zi-Qi Chen ◽  
Guo-Shan Ding ◽  
Zhi-Ren Fu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Ectopic Expression ◽  
Bioinformatic Analysis ◽  
Clinicopathological Characteristics ◽  
The Cancer Genome Atlas ◽  
Data Set ◽  
Small Noncoding Rnas ◽  
Normal Tissues ◽  
Potential Marker ◽  
Hcc Cells

MicroRNAs (miRNAs), a subgroup of small noncoding RNAs, play critical roles in tumor growth and metastasis. Accumulating evidence shows that the dysregulation of miRNAs is associated with the progression of hepatocellular carcinoma (HCC). However, the molecular mechanism by which miR-942-3p contributes to HCC remains undocumented. The association between miR-942-3p expression and the clinicopathological characteristics in HCC patients was analyzed by The Cancer Genome Atlas data set. The targets of miR-942-3p were identified by bioinformatic analysis and dual luciferase report assay. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Transwell assays were performed to assess the functional role of miR-942-3p in HCC cells. Consequently, we found that miR-942-3p expression level was elevated in HCC tissues and cell lines as compared with the normal tissues and was associated with the pathological stage and tumor node metastasis (TNM) stage, acting as an independent prognostic factor of poor survival in patients with HCC. Ectopic expression of miR-942-3p enhanced the proliferation and invasive potential of HCC cells, but inhibition of miR-942-3p expression had the opposite effects. Mannose-binding lectin 2 (MBL2) was further identified as a direct target of miR-942-3p and possessed a negative correlation with miR-942-3p expression and unfavorable survival in patients with HCC. Restoration of MBL2 inhibited the progression of HCC cells and attenuated the tumor-promoting effects induced by miR-942-3p. In conclusion, miR-942-3p may act as an oncogenic factor in HCC cells by targeting MBL2 and provide a potential marker for patients with HCC.

Liver Transplantation as a Therapeutic Option for Hepatocellular Carcinoma

Oncology ◽  
2002 ◽  
Vol 62 (Suppl. 1) ◽  
pp. 82-86 ◽  
Author(s):  
Hidetoshi Matsunami ◽  
Yasunobu Shimizu ◽  
Stephen V. Lynch ◽  
Glenda A. Balderson ◽  
Yuich Ando ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Transplantation ◽  
Therapeutic Option

MicroRNA-200a/b influenced the therapeutic effects of curcumin in hepatocellular carcinoma (HCC) cells

Tumor Biology ◽  
2013 ◽  
Vol 34 (5) ◽  
pp. 3209-3218 ◽  
Author(s):  
Hung-Hua Liang ◽  
Po-Li Wei ◽  
Chin-Sheng Hung ◽  
Chun-Te Wu ◽  
Weu Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Therapeutic Effects ◽  
Hcc Cells

The role of usnic acid-induced apoptosis and autophagy in hepatocellular carcinoma

2018 ◽  
Vol 38 (2) ◽  
pp. 201-215 ◽  
Author(s):  
B Yurdacan ◽  
U Egeli ◽  
G Guney Eskiler ◽  
IE Eryilmaz ◽  
G Cecener ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Death ◽  
Cell Lines ◽  
Cancer Cell ◽  
Usnic Acid ◽  
Genetic Profile ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Cell Type ◽  
Hcc Cells

Usnic acid (UA) is a multifunctional bioactive lichen secondary metabolite with potential anti-cancer properties. Although the promising therapeutic effects of UA have been investigated in different cancer cell lines, the mechanism driving UA-induced cell death has yet to be elucidated. As the type of cell death (apoptosis or autophagy) induced by UA may vary depending on the cancer cell type, we first studied the cytotoxic effects of UA in HEPG2 (HBV(−)) and SNU-449(HBV(+)) hepatocellular carcinoma (HCC) cell lines. HCC cell viability was considerably reduced in a dose-dependent manner at 12, 24, and 48 h after treatment with UA ( p < 0.05). However, SNU-449 cells were more sensitive to UA than HEPG2 cells. UA also induced apoptotic cell death in HCC cells with cell cycle arrest at G0/G1 and G2/M phase depending on the genetic profile of each cell type. On the other hand, we observed acidic vesicular organelles in HCC cells after 36 h of UA treatment. Taken together, these findings suggest that UA stimulates apoptosis and autophagy in HEPG2 and SNU-449 cells without damaging normal control cells. Thus, UA might be a potential therapeutic compound for HCC treatment. However, there is a need for further studies investigating the death-promoting or preventing roles for autophagy and the molecular signaling mechanisms induced by UA treatment.

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