scholarly journals Growth differentiation factor 1-induced tumour plasticity provides a therapeutic window for immunotherapy in hepatocellular carcinoma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wei Cheng ◽  
Hao-Long Li ◽  
Shao-Yan Xi ◽  
Xiao-Feng Zhang ◽  
Yun Zhu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Checkpoint Inhibitors ◽  
Ectopic Expression ◽  
Therapeutic Window ◽  
Cancer Testis Antigens ◽  
Differentiation Factor ◽  
Lysine Specific Demethylase ◽  
Receptor Like Kinase ◽  
Developmental Signalling ◽  
Hcc Cells

AbstractTumour lineage plasticity is an emerging hallmark of aggressive tumours. Tumour cells usually hijack developmental signalling pathways to gain cellular plasticity and evade therapeutic targeting. In the present study, the secreted protein growth and differentiation factor 1 (GDF1) is found to be closely associated with poor tumour differentiation. Overexpression of GDF1 suppresses cell proliferation but strongly enhances tumour dissemination and metastasis. Ectopic expression of GDF1 can induce the dedifferentiation of hepatocellular carcinoma (HCC) cells into their ancestral lineages and reactivate a broad panel of cancer testis antigens (CTAs), which further stimulate the immunogenicity of HCC cells to immune-based therapies. Mechanistic studies reveal that GDF1 functions through the Activin receptor-like kinase 7 (ALK7)-Mothers against decapentaplegic homolog 2/3 (SMAD2/3) signalling cascade and suppresses the epigenetic regulator Lysine specific demethylase 1 (LSD1) to boost CTA expression. GDF1-induced tumour lineage plasticity might be an Achilles heel for HCC immunotherapy. Inhibition of LSD1 based on GDF1 biomarker prescreening might widen the therapeutic window for immune checkpoint inhibitors in the clinic.

scholarly journals MiR-424-5p regulates cell cycle and inhibits proliferation of hepatocellular carcinoma cells by targeting E2F7

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0242179
Author(s):  
Yichao Zhao ◽  
Chaoqian Zhu ◽  
Qing Chang ◽  
Peng Peng ◽  
Jie Yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Flow Cytometry ◽  
Ectopic Expression ◽  
Luciferase Reporter Assay ◽  
Luciferase Reporter ◽  
G1 Phase ◽  
Reporter Assay ◽  
Hcc Cells ◽  
Dual Luciferase Reporter Assay

Objective This study aims to explore the mechanism of the miR-424-5p/E2F7 axis in hepatocellular carcinoma (HCC) and provide new ideas for targeted therapy of HCC. Methods Bioinformatics analysis was used to identify the target differentially expressed miRNA in HCC and predict its target gene. qRT-PCR was employed to verify the expression of miR-424-5p and E2F7 mRNA in HCC cells. Western blot was performed to detect the effect of miR-424-5p ectopic expression on the protein expression of E2F7. CCK-8 was used to detect proliferative activity of HCC cells and flow cytometry was carried out for analyzing cell cycle distribution. Dual luciferase reporter assay was conducted to verify the direct targeting relationship between miR-424-5p and E2F7. Results We observed that miR-424-5p was down-regulated in HCC cells. CCK-8 showed that overexpression of miR-424-5p inhibited cell proliferation, and flow cytometry showed that miR-424-5p could block cells in G0/G1 phase. E2F7 was up-regulated in HCC cells, and E2F7 overexpression could facilitate the proliferative ability of HCC cells and promote the cell cycle progressing from G0/G1 to S phase. Furthermore, dual-luciferase reporter assay indicated that miR-424-5p could directly down-regulate E2F7 expression. Analysis on cell function demonstrated that miR-424-5p inhibited the proliferation of HCC cells and blocked cell cycle at G0/G1 phase by targeting E2F7. Conclusion Our results proved that E2F7 was a direct target of miR-424-5p, and miR-424-5p could regulate cell cycle and further inhibit the proliferation of HCC cells by targeting E2F7.

scholarly journals B-Cell Receptor-Associated Protein 31 Promotes Metastasis via AKT/β-Catenin/Snail Pathway in Hepatocellular Carcinoma

2021 ◽  
Vol 8 ◽  
Author(s):  
Tengfei Liu ◽  
Junming Yu ◽  
Chao Ge ◽  
Fangyu Zhao ◽  
Chunxiao Miao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Cell Receptor ◽  
Migration And Invasion ◽  
Related Factor ◽  
Akt Inhibitor ◽  
Mesenchymal Transition ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is one of the most lethal cancer worldwide, characterized with high heterogeneity and inclination to metastasize. Emerging evidence suggests that BAP31 gets involved in cancer progression with different kinds. It still remains unknown whether and how BAP31 plays a role in HCC metastasis. Epithelial–mesenchymal transition (EMT) has been a common feature in tumor micro-environment, whose inducer TGF-β increased BAP31 expression in this research. Elevated expression of BAP31 was positively correlated with tumor size, vascular invasion and poor prognosis in human HCC. Ectopic expression of BAP31 promoted cell migration and invasion while BAP31 knockdown markedly attenuated metastatic potential in HCC cells and mice orthotopic xenografts. BAP31 induced EMT process, and enhanced the expression level of EMT-related factor Snail and decreased contents and membrane distribution of E-cadherin. BAP31 also activated AKT/β-catenin pathway, which mediated its promotional effects on HCC metastasis. AKT inhibitor further counteracted the activated AKT/β-catenin/Snail upon BAP31 over-expression. Moreover, silencing Snail in BAP31-overexpressed cells impaired enhanced migratory and invasive abilities of HCC cells. In HCC tissues, BAP31 expression was positively associated with Snail. In conclusion, BAP31 promotes HCC metastasis by activating AKT/β-catenin/Snail pathway. Thus, our study implicates BAP31 as potential prognostic biomarker, and provides valuable information for HCC prognosis and treatment.

scholarly journals PRCC reduces the sensitivity of cancer cells to DNA damage by inhibiting JNK and ATM/ATR pathways and results in a poor prognosis in hepatocellular carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Chunying Liu ◽  
Xuejing Lin ◽  
Bin Sun ◽  
Ziming Mao ◽  
Lei Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dna Damage ◽  
Cancer Cells ◽  
Clinical Diagnosis ◽  
Poor Prognosis ◽  
Ectopic Expression ◽  
Mitotic Checkpoint ◽  
Application Potential ◽  
Hcc Cells ◽  
High Application

Abstract Background and aim The proline rich mitotic checkpoint control factor (PRCC) is involved in the splicing process of pre-mRNA. This study aims to elucidate PRCC molecular function, regulatory mechanism and diagnostic value in hepatocellular carcinoma (HCC). Methods The tissue microarray and serum samples from HCC patients were used to investigate the clinical value of PRCC. The biological function and molecular mechanism of PRCC were demonstrated by cell biology, biochemical and animal experiments. The relationship between PRCC and intratumoral heterogeneity (ITH) was analyzed by bioinformatics. Results PRCC was highly expressed in HCC tissues and related to the poor prognosis of HCC patients, its contents were elevated in the preoperative sera of HCC patients. PRCC exhibited high application potential as a substitute or adjuvant of alpha-fetoprotein (AFP) for clinical diagnosis of HCC. It had no significant effect on the proliferation of cancer cells, but could inhibit spheroid formation and metastasis of HCC cells in vitro and in vivo. The high ectopic expression of PRCC made cancer cells insensitive to DNA damage, and enhanced the heterogeneity of HCC cells by inhibiting the JNK/ATM/ATR/ATF2 axis. The HCC patients with high PRCC expression had high ITH, which corresponded to a short overall survival in patients. Conclusions PRCC has high application potential as a substitute or adjuvant of AFP for clinical diagnosis of HCC. The high ectopic expression of PRCC not only caused HCC cells to resist to cell death induced by DNA damage, but also endowed cancer cells with numerous DNA mutations to become increasingly heterogeneous, finally leading to a poor prognosis in HCC patients. These data suggested PRCC could be a promising therapeutic target in HCC patients.

scholarly journals DEAH-box polypeptide 32 promotes hepatocellular carcinoma progression via activating the β-catenin pathway

2020 ◽  
Author(s):  
Xiaoyun Hu ◽  
Guosheng Yuan ◽  
Qi Li ◽  
Jing Huang ◽  
Xiao Cheng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Ectopic Expression ◽  
Migration And Invasion ◽  
High Morbidity ◽  
Rt Pcr ◽  
Mesenchymal Transition ◽  
Potential Biomarker ◽  
Hcc Cells

Abstract Background Hepatocellular carcinoma (HCC) is a refractory cancer with high morbidity and high mortality. It has been reported that DEAH-box polypeptide 32 (DHX32) was upregulated in several types of malignancies and predicted poor prognosis, which was associated with tumor growth and metastasis. However, the expression of DHX32 in HCC and its role in HCC progression remain largely unknown. Methods Western blot and RT-PCR assays were used to detect the expression of DHX32 and epithelial mesenchymal transition (EMT)-related genes in HCC cells. Wound-healing and Transwell invasion assays were performed to determine the effect of DHX32 and β-catenin on the migration and invasion of HCC cells. Cell proliferation was examined by EdU cell proliferation assay. Results In our study, we found that high level of DHX32 expression was associated with reduced overall survival in HCC patients. DHX32 expression was upregulated in human HCC cells and ectopic expression of DHX32 induced EMT, promoted the migration, invasion, and proliferation of HCC cells, and enhanced tumor growth. Silencing DHX32 reversed EMT, inhibited the migration, invasion, and proliferation of HCC cells, and suppressed tumor growth. RT-PCR assay revealed that DHX32 regulated the expression of CTNNB1, CCND1, COX2, MMP7, and WIF1 in HCC cells. Mechanistic investigations showed that silencing DHX32 decreased the expression of β-catenin in nucleus and β-catenin siRNA abrogated DHX32-mediated EMT, migration, invasion, and proliferation in HCC cells. Conclusions Our data suggested that DHX32 was an attractive regulator of HCC progression and indicated DHX32 can serve as a potential biomarker and therapeutic target for HCC patients.

scholarly journals ENO3 Inhibits Growth and Metastasis of Hepatocellular Carcinoma via Wnt/β-Catenin Signaling Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Honglei Cui ◽  
Danfeng Guo ◽  
Xiaodan Zhang ◽  
Yaohua Zhu ◽  
Zhihui Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Noncancerous Tissue ◽  
Mesenchymal Transition ◽  
Proliferation And Metastasis ◽  
Hcc Cells

β-enolase (ENO3) is a metalloenzyme that functions during glycolysis and has been revealed ectopic expression in different cancers. However, the function and underlying modulatory mechanisms of ENO3 in hepatocellular carcinoma (HCC) are still elusive. Here, we discovered that ENO3 was remarkably down-regulated in human HCC tissue in contrast to those in noncancerous tissue. Moreover, low expression of ENO3 was related to the poor prognosis of HCC patients. Overexpression of ENO3 suppressed proliferative, migratory, and invasive abilities of HCC cells both in vitro and in vivo, whereas knocking down ENO3 led to the opposite effect. In addition, we revealed that ENO3 repressed the epithelial-mesenchymal transition (EMT) process with its biomarker variations. Mechanistic research unveiled that ENO3 suppressed the Wnt/β-catenin signal, which subsequently modulated the transcription of its target genes associated with the proliferation and metastasis capacity of HCC cells. Taken together, our study uncovered that ENO3 acted as a tumor inhibitor in HCC development and implied ENO3 as a promising candidate for HCC treatment.

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.

scholarly journals Harnessing immunotherapy for liver recipients with hepatocellular carcinoma: a review from a transplant oncology perspective

2019 ◽  
Vol 11 ◽  
pp. 175883591984346 ◽  
Author(s):  
Cheng-Maw Ho ◽  
Hui-Ling Chen ◽  
Rey-Heng Hu ◽  
Po-Huang Lee
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cell ◽  
Checkpoint Inhibitors ◽  
Interleukin 2 ◽  
Cell Activity ◽  
Cancer Recurrence ◽  
Receptor Occupancy ◽  
Therapeutic Window ◽  
Immune Microenvironment ◽  
Hcc Recurrence

Without stringent criteria, liver transplantation for hepatocellular carcinoma (HCC) can lead to high cancer recurrence and poor prognosis in the current treatment context. Checkpoint inhibitors can lead to long survival by targeting coinhibitory pathways and promoting T-cell activity; thus, they have great potential for cancer immunotherapy. Therapeutic modulation of cosignaling pathways may shift paradigms from surgical prevention of recurrence to oncological intervention. Herein, we review the available evidence from a therapeutic perspective and focus on immune microenvironment perturbation by immunosuppressants and checkpoint inhibitors. Partial and reversible interleukin-2 signaling blockade is the mainstream strategy of immunosuppression for graft protection. Programmed cell death protein 1 (PD-1) is abundantly expressed on human liver allograft-infiltrating T-cells, which proliferate considerably after programmed death-ligand 1 (PD-L1) blockade. Clinically, checkpoint inhibitors are used in heart, liver, and kidney recipients with various cancers. Rejection can occur after checkpoint inhibitor administration through acute T-cell-mediated, antibody-mediated, or chronic allograft rejection mechanisms. Nevertheless, liver recipients may demonstrate favorable responses to treatment for HCC recurrence without rejection. Pharmacodynamically, substantial degrees of receptor occupancy can be achieved with lower doses, with favorable clinical outcomes. Manipulation of the immune microenvironment is a therapeutic niche that balances seemingly conflicting anticancer and graft protection needs. Additional translational and clinical studies emphasizing the comparative effectiveness of signaling networks within the immune microenvironment and conducting overall assessment of the immune microenvironment may aid in creating a therapeutic window and benefiting future liver recipients with HCC recurrence.

scholarly journals Long non-coding RNA MAPKAPK5-AS1/PLAGL2/HIF-1α signaling loop promotes hepatocellular carcinoma progression

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Liang Wang ◽  
Liankang Sun ◽  
Runkun Liu ◽  
Huanye Mo ◽  
Yongshen Niu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Hypoxia Inducible Factor ◽  
Ectopic Expression ◽  
Akt Signaling ◽  
Luciferase Reporter ◽  
Mesenchymal Transition ◽  
Hcc Cells

Abstract Background Long non-coding RNAs (lncRNAs) are widely involved in human cancers’ progression by regulating tumor cells’ various malignant behaviors. MAPKAPK5-AS1 has been recognized as an oncogene in colorectal cancer. However, the biological role of MAPKAPK5-AS1 in hepatocellular carcinoma (HCC) has not been explored. Methods Quantitative real-time PCR was performed to detect the level of MAPKAPK5-AS1 in HCC tissues and cell lines. The effects of MAPKAPK5-AS1 on tumor growth and metastasis were assessed via in vitro experiments, including MTT, colony formation, EdU, flow cytometry, transwell assays, and nude mice models. The western blotting analysis was carried out to determine epithelial-mesenchymal transition (EMT) markers and AKT signaling. The interaction between MAPKAPK5-AS1, miR-154-5p, and PLAGL2 were explored by luciferase reporter assay and RNA immunoprecipitation. The regulatory effect of HIF-1α on MAPKAPK5-AS1 was evaluated by chromatin immunoprecipitation. Results MAPKAPK5-AS1 expression was significantly elevated in HCC, and its overexpression associated with malignant clinical features and reduced survival. Functionally, MAPKAPK5-AS1 knockdown repressed the proliferation, mobility, and EMT of HCC cells and induced apoptosis. Ectopic expression of MAPKAPK5-AS1 contributed to HCC cell proliferation and invasion in vitro. Furthermore, MAPKAPK5-AS1 silencing suppressed, while MAPKAPK5-AS1 overexpression enhanced HCC growth and lung metastasis in vivo. Mechanistically, MAPKAPK5-AS1 upregulated PLAG1 like zinc finger 2 (PLAGL2) expression by acting as an endogenous competing RNA (ceRNA) to sponge miR-154-5p, thereby activating EGFR/AKT signaling. Importantly, rescue experiments demonstrated that the miR-154-5p/PLAGL2 axis mediated the function of MAPKAPK5-AS1 in HCC cells. Interestingly, we found that hypoxia-inducible factor 1α (HIF-1α), a transcript factor, could directly bind to the promoter to activate MAPKAPK5-AS1 transcription. MAPKAPK5-AS1 regulated HIF-1α expression through PLAGL2 to form a hypoxia-mediated MAPKAPK5-AS1/PLAGL2/HIF-1α signaling loop in HCC. Conclusions Our results reveal a MAPKAPK5-AS1/PLAGL2/HIF-1α signaling loop in HCC progression and suggest that MAPKAPK5-AS1 could be a potential novel therapeutic target of HCC.

scholarly journals TROAP switches DYRK1 activity to drive hepatocellular carcinoma progression

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lei Li ◽  
Jia-Ru Wei ◽  
Ye Song ◽  
Shuo Fang ◽  
Yanyu Du ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Ectopic Expression ◽  
Prognostic Indicator ◽  
Soft Agar ◽  
Mechanistic Investigation ◽  
Gsk 3Β ◽  
High Level ◽  
Hcc Cells

AbstractHepatocellular carcinoma (HCC) is one of the common malignancy and lacks effective therapeutic targets. Here, we demonstrated that ectopic expression of trophinin-associated protein (TROAP) dramatically drove HCC cell growth assessed by foci formation in monolayer culture, colony formation in soft agar and orthotopic liver transplantation in nude mice. Inversely, silencing TROAP expression with short-hairpin RNA attenuated the malignant proliferation of HCC cells in vitro and in vivo. Next, mechanistic investigation revealed that TROAP directly bound to dual specificity tyrosine phosphorylation regulated kinase 1A/B (DYRK1A/B), resulting in the cytoplasmic retention of proteins DYRK1A/B and promoting cell cycle process via activation of Akt/GSK-3β signaling. Combination of cisplatin with an inhibitor of DYRK1 AZ191 effectively inhibited tumor growth in mouse model for HCC cells with high level of TROAP. Clinically, TROAP was significantly upregulated by miR-142-5p in HCC tissues, which predicted the poor survival of patients with HCC. Therefore, TROAP/DYRK1/Akt axis may be a promising therapeutic target and prognostic indicator for patients with HCC.

Immune checkpoint and checkpoint inhibitors in hepatocellular carcinoma

2018 ◽  
Vol 1 (1) ◽  
pp. 28-32
Author(s):  
Piyawat Komolmit
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell Receptor ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cell Receptor ◽  
Immune Checkpoints ◽  
Histocompatibility Complex

การรักษามะเร็งด้วยแนวความคิดของการกระตุ้นให้ภูมิต้านทานของร่างกายไปทำลายเซลล์มะเร็งนั้น ปัจจุบันได้รับการพิสูจน์ชัดว่าวิธีการนี้สามารถหยุดยั้งการแพร่กระจายของเซลล์มะเร็ง โดยไม่ก่อให้เกิดภาวะแทรกซ้อนทางปฏิกิริยาภูมิต้านทานต่ออวัยวะส่วนอื่นที่รุนแรง สามารถนำมาใช้ทางคลินิกได้ ยุคของการรักษามะเร็งกำลังเปลี่ยนจากยุคของยาเคมีบำบัดเข้าสู่การรักษาด้วยภูมิต้านทาน หรือ immunotherapy ยากลุ่ม Immune checkpoint inhibitors โดยเฉพาะ PD-1 กับ CTLA-4 inhibitors จะเข้ามามีบทบาทในการรักษามะเร็งตับในระยะเวลาอันใกล้ จำเป็นแพทย์จะต้องมีความรู้ความเข้าใจในพื้นฐานของ immune checkpoints และยาที่ไปยับยั้งโมเลกุลเหล่านี้ Figure 1 เมื่อ T cells รับรู้แอนทิเจนผ่านทาง TCR/MHC จะมีปฏิกิริยาระหว่าง co-receptors หรือ immune checkpoints กับ ligands บน APCs หรือ เซลล์มะเร็ง ทั้งแบบกระตุ้น (co-stimulation) หรือยับยั้ง (co-inhibition) TCR = T cell receptor, MHC = major histocompatibility complex

Sign in / Sign up

Export Citation Format

Share Document