scholarly journals Metabolic alterations and vulnerabilities in hepatocellular carcinoma

2020 ◽  
Author(s):  
Daniel G Tenen ◽  
Li Chai ◽  
Justin L Tan
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Current Literature ◽  
Primary Site ◽  
The Body ◽  
Therapeutic Interventions ◽  
Metabolic Alterations ◽  
Underlying Mechanisms ◽  
Serious Disease ◽  
Hcc Cells

Abstract Liver cancer is a serious disease. It is ranked as the cancer with the second highest number of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC), which arises from transformed hepatocytes, is the major subtype of liver cancer. It accounts for 85% of total liver-cancer cases. An important aspect of HCC that has been actively studied is its metabolism. With the liver as the primary site of numerous metabolic processes in the body, it has been shown that the metabolism of HCC cells is highly dysregulated compared to that of normal hepatocytes. It is therefore crucial to understand the metabolic alterations caused by HCC and the underlying mechanisms for these alterations. This deeper understanding will allow diagnostic and therapeutic advancements in the treatment of HCC. In this review, we will summarize the current literature in HCC metabolic alterations, induced vulnerabilities, and potential therapeutic interventions.

Silencing non-SMC chromosome-associated polypeptide G inhibits proliferation and induces apoptosis in hepatocellular carcinoma cells

2018 ◽  
Vol 96 (12) ◽  
pp. 1246-1254 ◽  
Author(s):  
Kaikun Liu ◽  
Yumin Li ◽  
Bo Yu ◽  
Furong Wang ◽  
Taiyu Mi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Liver Cancer ◽  
Protein Expression ◽  
Mrna Expression ◽  
Mrna Level ◽  
A Subunit ◽  
Underlying Mechanisms ◽  
Colony Forming Capacity ◽  
Hcc Cells

The present study was designed to investigate the significance of non–structural maintenance of chromosomes (non-SMC) chromosome-associated polypeptide G (NCAPG), a subunit of condensin complex I, in the development of hepatocellular carcinoma (HCC). NCAPG protein expression in human HCC and paracancerous hepatic tissues were examined using immunohistochemistry, and NCAPG mRNA expression in HCC cell lines were quantified using quantitative RT–PCR. Lentivirus-mediated RNA interference was used to silence NCAPG in HCC cells. Cell proliferation was monitored by MTT assay. Cell colony-forming capacity was measured by colony formation assay. Apoptosis was determined by flow cytometry. The results showed that increased protein expression of NCAPG was found in HCC tissues compared with the matched paracancerous hepatic tissues. At the mRNA level, increased expression of NCAPG was found in HCC cells as opposed to the normal hepatocytes. Silencing of NCAPG in BEL-7404 and SMMC-7721 cells led to decreased cell proliferation and increased apoptosis. These changes were associated with increased mRNA expressions of P53, P27, and Bad, but decreased mRNA expression of EGFR, Akt, survivin, and JNK. NCAPG might play an oncogenic role in the development of liver cancer. Further studies to clarify its role and underlying mechanisms in the development of liver cancer are warranted.

scholarly journals Argininosuccinate synthase 1 suppresses tumor progression through activation of PERK/eIF2α/ATF4/CHOP axis in hepatocellular carcinoma

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Sanghwa Kim ◽  
Minji Lee ◽  
Yeonhwa Song ◽  
Su-Yeon Lee ◽  
Inhee Choi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Er Stress ◽  
Stress Responses ◽  
Arginine Metabolism ◽  
Tumor Spheroids ◽  
Clinical Value ◽  
Suppressor Activity ◽  
Argininosuccinate Synthase ◽  
Hcc Cells

Abstract Background Hepatocellular carcinoma (HCC) is one of the most common malignant cancers worldwide, and liver cancer has increased in mortality due to liver cancer because it was detected at an advanced stages in patients with liver dysfunction, making HCC a lethal cancer. Accordingly, we aim to new targets for HCC drug discovery using HCC tumor spheroids. Methods Our comparative proteomic analysis of HCC cells grown in culture as monolayers (2D) and spheroids (3D) revealed that argininosuccinate synthase 1 (ASS1) expression was higher in 3D cells than in 2D cells due to upregulated endoplasmic reticulum (ER) stress responses. We investigated the clinical value of ASS1 in Korean patients with HCC. The mechanism underlying ASS1-mediated tumor suppression was investigated in HCC spheroids. ASS1-mediated improvement of chemotherapy efficiency was observed using high content screening in an HCC xenograft mouse model. Results Studies of tumor tissue from Korean HCC patients showed that, although ASS1 expression was low in most samples, high levels of ASS1 were associated with favorable overall survival of patients. Here, we found that bidirectional interactions between ASS1 ER stress responses in HCC-derived multicellular tumor spheroids can limit HCC progression. ASS1 overexpression effectively inhibited tumor growth and enhanced the efficacy of in vitro and in vivo anti-HCC combination chemotherapy via activation of the PERK/eIF2α/ATF4/CHOP axis, but was not dependent on the status of p53 and arginine metabolism. Conclusions These results demonstrate the critical functional roles for the arginine metabolism–independent tumor suppressor activity of ASS1 in HCC and suggest that upregulating ASS1 in these tumors is a potential strategy in HCC cells with low ASS1 expression.

scholarly journals Lipid Metabolic Reprogramming in Hepatocellular Carcinoma

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 447 ◽  
Author(s):  
Hayato Nakagawa ◽  
Yuki Hayata ◽  
Satoshi Kawamura ◽  
Tomoharu Yamada ◽  
Naoto Fujiwara ◽  
...  
Keyword(s):  
Risk Factors ◽  
Hepatocellular Carcinoma ◽  
Local Environment ◽  
Metabolic Reprogramming ◽  
Glutamine Metabolism ◽  
Metabolic Alterations ◽  
Rich Condition ◽  
Visceral Adipose ◽  
Hcc Cells

Metabolic reprogramming for adaptation to the local environment has been recognized as a hallmark of cancer. Although alterations in fatty acid (FA) metabolism in cancer cells have received less attention compared to other metabolic alterations such as glucose or glutamine metabolism, recent studies have uncovered the importance of lipid metabolic reprogramming in carcinogenesis. Obesity and nonalcoholic steatohepatitis (NASH) are well-known risk factors of hepatocellular carcinoma (HCC), and individuals with these conditions exhibit an increased intake of dietary FAs accompanied by enhanced lipolysis of visceral adipose tissue due to insulin resistance, resulting in enormous exogenous FA supplies to hepatocytes via the portal vein and lymph vessels. This “lipid-rich condition” is highly characteristic of obesity- and NASH-driven HCC. Although the way in which HCC cells adapt to such a condition and exploit it to aid their progression is not understood, we recently obtained new insights into this mechanism through lipid metabolic reprogramming. In addition, accumulating evidence supports the importance of lipid metabolic reprogramming in various situations of hepatocarcinogenesis. Thus, in this review, we discuss the latest findings regarding the role of FA metabolism pathways in hepatocarcinogenesis, focusing on obesity- and NASH-driven lipid metabolic reprogramming.

Quantitative proteomics identifies FOLR1 to drive sorafenib resistance via activating autophagy in hepatocellular carcinoma cells

2021 ◽  
Author(s):  
Hongwei Chu ◽  
Changqing Wu ◽  
Qun Zhao ◽  
Rui Sun ◽  
Kuo Yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Folate Receptor ◽  
Mass Spectrometry Analysis ◽  
Label Free ◽  
Spectrometry Analysis ◽  
Underlying Mechanisms ◽  
Related Proteins ◽  
Hcc Cells

Abstract Sorafenib is commonly used to treat advanced human hepatocellular carcinoma (HCC). However, clinical efficacy has been limited by drug resistance. In this study, we used label-free quantitative proteomic analysis to systematically investigate the underlying mechanisms of sorafenib resistance in HCC cells. A total of 1709 proteins were confidently quantified. Among them, 89 were differentially expressed, and highly enriched in the processes of cell-cell adhesion, negative regulation of apoptosis, response to drug and metabolic processes involving in sorafenib resistance. Notably, folate receptor α (FOLR1) was found to be significantly upregulated in resistant HCC cells. In addition, in-vitro studies showed that overexpression of FOLR1 decreased the sensitivity of HCC cells to sorafenib, whereas siRNA-directed knockdown of FOLR1 increased the sensitivity of HCC cells to sorafenib. Immunoprecipitation-mass spectrometry analysis suggested a strong link between FOLR1 and autophagy related proteins. Further biological experiments found that FOLR1-related sorafenib resistance was accompanied by the activation of autophagy, whereas inhibition of autophagy significantly reduced FOLR1-induced cell resistance. These results suggest the driving role of FOLR1 in HCC resistance to sorafenib, which may be exerted through FOLR1-induced autophagy. Therefore, this study may provide new insights into understanding the mechanism of sorafenib resistance.

scholarly journals As a downstream target of the AKT pathway, NPTX1 inhibits proliferation and promotes apoptosis in hepatocellular carcinoma

2019 ◽  
Vol 39 (6) ◽  
Author(s):  
Yue Zhao ◽  
Yaqi Yu ◽  
Wenxiu Zhao ◽  
Song You ◽  
Min Feng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Akt Pathway ◽  
Serine Threonine Kinase ◽  
Signaling Mechanism ◽  
Downstream Target ◽  
Clinicopathological Significance ◽  
Neuronal Pentraxin ◽  
Underlying Mechanisms ◽  
And Function ◽  
Hcc Cells

Abstract Hepatocellular carcinoma (HCC) is correlated with a poor prognosis and high mortality worldwide. Neuronal pentraxin 1 (NPTX1) has been reported to play an oncogenic role in several types of tumors. However, its expression and function in HCC is not yet fully understood. In the present study, we aimed to investigate the clinicopathological significance of NPTX1 in HCC and the underlying mechanisms. We observed that the expression of NPTX1 was decreased significantly in HCC and was associated with tumor size and metastasis in patients. Gain-of-function approaches revealed that NPTX1 suppressed the growth ability of HCC cells and contributed to mitochondria- related apoptosis. Furthermore, mechanistic investigations showed that the AKT (AKT serine/threonine kinase) pathway can regulate the effects of NPTX1 in HCC cells. After blocking the AKT pathway, the action of NPTX1 was greatly increased. In summary, we demonstrated that NPTX1 inhibited growth and promoted apoptosis in HCC via an AKT-mediated signaling mechanism. These findings indicate that NPTX1 is a potential clinical therapeutic target.

scholarly journals Overexpression of Uric Acid Transporter SLC2A9 Inhibits Proliferation of Hepatocellular Carcinoma Cells

2019 ◽  
Vol 27 (5) ◽  
pp. 533-540 ◽  
Author(s):  
Xiaoying Han ◽  
Jing Yang ◽  
Dong Li ◽  
Zewei Guo
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Uric Acid ◽  
Tumor Suppressor ◽  
Cell Apoptosis ◽  
Suppressor Gene ◽  
Potential Contribution ◽  
Acid Transporter ◽  
Underlying Mechanisms ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-associated mortality worldwide. Although the mechanisms of HCC progression are not well understood, recent studies demonstrated the potential contribution of uric acid transporter SLC2A9 to tumor suppression. However, the roles and underlying mechanisms are still unknown. We aimed to study the roles and mechanisms of SLC2A9 in HCC. The present study showed that SLC2A9 expression was decreased in human HCC tissues and cell lines. In addition, overexpression of SLC2A9 inhibited HCC cell proliferation. SCL2A9 induced HCC cell apoptosis by inhibiting the expression of caspase 3. Our study also revealed that upregulation of SLC2A9 reduced intracellular reactive oxygen species (ROS) accumulation. Furthermore, SLC2A9 increased the mRNA and protein expression of tumor suppressor p53 in HCC cells. Probenecid inhibits SLC2A9-mediated uric acid transport, which promotes cell proliferation, inhibits cell apoptosis, induces intracellular ROS, and decreases the expression of p53 in HCC cells. Therefore, the present study demonstrated that SLC2A9 may be a novel tumor suppressor gene and a potential therapeutic target in HCC.

Highly fluorescent QD probes labeling hepatocellular carcinoma cells

RSC Advances ◽  
2015 ◽  
Vol 5 (3) ◽  
pp. 1841-1845 ◽  
Author(s):  
Baiqi Wang ◽  
Hetao Chen ◽  
Rui Yang ◽  
Fang Wang ◽  
Ping Zhou ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Cancer Cells ◽  
Carcinoma Cells ◽  
Hepatocellular Carcinoma Cells ◽  
Liver Cancer Cells ◽  
Hcc Cells

The red signals from the cytoplasm of HCC cells reveal that the QD probes can specifically label liver cancer cells.

scholarly journals LncRNA-URHC Functions as a ceRNA to Regulate Danjb9 Expression by Competitively Binding to miR-5007-3p in Hepatocellular Carcinoma

2021 ◽  
Author(s):  
kunwei niu ◽  
Shibin Qu ◽  
Xuan Zhang ◽  
Jimin Dai ◽  
Jianlin Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Biological Effects ◽  
Luciferase Reporter ◽  
Underlying Mechanisms ◽  
Proliferation In Vitro ◽  
Hcc Cells

Abstract Background: Hepatocellular carcinoma (HCC) is often diagnosed at a late stage, when the prognosis is poor. The regulation of long non-coding RNAs (lncRNAs) plays a crucial role in HCC. However, the precise regulatory mechanisms of lncRNA signaling in HCC remain largely unknown. We study aim to investigate the underlying mechanisms of lncRNA (upregulated in hepatocellular carcinoma) URHC in HCC. Methods: RT-qPCR, fluorescence in situ hybridization (FISH) staining, EdU, colony formation, and tumor xenografts experiments were used to identify localized and biological effects of URHC on HCC cells in vitro and in vivo. The bioinformatics analysis, Dual-luciferase reporter assay, and rescue experiments revealed the potential mechanism of URHC.Results: URHC silencing may inhibit the HCC cells proliferation in vitro and in vivo. We found that URHC was mainly localized in the cytoplasm. The expression of miR-5007-3p was negatively regulated by URHC. And miR-5007-3p could reverse the effect of URHC in HCC cells. The expression of DNAJB9 was negatively regulated by miR-5007-3p but positively regulated by URHC. These suggesting of lncRNA-URHC positively regulated the level of DNAJB9 by sponging miR-5007-3p.Conclusion: Together, our study elucidated the role of URHC as a miRNA sponge in HCC, and shed new light on lncRNA-directed diagnostics and therapeutics in HCC.

scholarly journals New Advances in Tissue Metabolomics: A Review

Metabolites ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 672
Author(s):  
Michelle Saoi ◽  
Philip Britz-McKibbin
Keyword(s):  
Biomarker Discovery ◽  
Clinical Medicine ◽  
Ex Vivo ◽  
Diagnostic Testing ◽  
The Body ◽  
Therapeutic Interventions ◽  
Organ Specific ◽  
Human Participants ◽  
Underlying Mechanisms ◽  
Tissue Specimens

Metabolomics offers a hypothesis-generating approach for biomarker discovery in clinical medicine while also providing better understanding of the underlying mechanisms of chronic diseases. Clinical metabolomic studies largely rely on human biofluids (e.g., plasma, urine) as a more convenient specimen type for investigation. However, biofluids are non-organ specific reflecting complex biochemical processes throughout the body, which may complicate biochemical interpretations. For these reasons, tissue metabolomic studies enable deeper insights into aberrant metabolism occurring at the direct site of disease pathogenesis. This review highlights new advances in metabolomics for ex vivo analysis, as well as in situ imaging of tissue specimens, including diverse tissue types from animal models and human participants. Moreover, we discuss key pre-analytical and post-analytical challenges in tissue metabolomics for robust biomarker discovery with a focus on new methodological advances introduced over the past six years, including innovative clinical applications for improved screening, diagnostic testing, and therapeutic interventions for cancer.

scholarly journals Telocytes Promote the Metastasis of Hepatocellular Carcinoma by Activating ERK Signaling Pathway and Sponging miR-942-3p to Impact MMP9

2021 ◽  
Author(s):  
Ying Xu ◽  
Hu Tian ◽  
Chao Guang Luan ◽  
Kai Sun ◽  
peng Jin Bao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Signaling Pathway ◽  
Erk Signaling ◽  
Cancer Tissue ◽  
Proliferative Potential ◽  
Cancer Tissues ◽  
Hcc Cells

Abstract Background: Hepatocellular carcinoma(HCC) in China is considered as a familiar malignant tumor with poor prognosis, high metastasis and disease relapse. Telocytes(TCs) have been verified to participate in progresses of tumorigenesis, invasions and migrations by secreting functional proteins and transmitting cell-to-cell information. Extracellular signal-regulared protein kinase(ERK) signal pathway is a vital mechanism driving cell proliferation, metastasis and apoptosis, but whether this molecular signaling mechanism contributes to matrix metalloproteinase-9(MMP) expression of TCs remains unclear. Methods: Telocytes and MMP9 expression in the liver cancer tissues are measured by immunohistochemistry assay, Westen blot assay and RT-PCR technique, meanwhile primary telocytes from liver para-cancer tissues are cultured in vitro. To demonstrate the function of telocytes for hepatocellular carcinoma, the metastatic cancer animal model is established by three typs of liver cancer cell-lines in vivo. Results: In our study, we elucidate that TCs in the para-cancer tissue can promote the metastasis of HCC cells by MMP-9 expression, in vitro and in vivo. PDGF derived from HCC cells has a capacity to activate Ras/ERK signaling pathway of TC as a result of accelerating MMP-9 expression, but it’s no significant for proliferative potential and apoptotic rate of TCs. While tyrosine kinase inhibitors and miR-942-3p suppress MMP-9 expression to make loss functions of TCs. Various mutations of TCs are also tested and single nucleotide polymorphisms of MMP-9 may be the potentially molecular mechanism of increasing protein expression in the invasive process of HCC. Conclusion: Our results demonstrate two potential mechanisms between HCC cells and TCs, suggesting that TC is a novel marker and target on deciphering reasons of cancer metastasis.

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