scholarly journals Intermedin facilitates hepatocellular carcinoma cell survival and invasion via ERK1/2-EGR1/DDIT3 signaling cascade

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Fei Xiao ◽  
Hongyu Li ◽  
Zhongxue Feng ◽  
Luping Huang ◽  
Lingmiao Kong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Er Stress ◽  
Cell Survival ◽  
Vascular Remodeling ◽  
Therapeutic Potential ◽  
Blood Perfusion ◽  
Signaling Cascade ◽  
Apoptotic Pathway ◽  
High Level ◽  
Hcc Cells

AbstractAs one of the most malignant cancer types, hepatocellular carcinoma (HCC) is highly invasive and capable of metastasizing to distant organs. Intermedin (IMD), an endogenous peptide belonging to the calcitonin family, has been suggested playing important roles in cancer cell survival and invasion, including in HCC. However, how IMD affects the behavior of HCC cells and the underlying mechanisms have not been fully elucidated. Here, we show that IMD maintains an important homeostatic state by activating the ERK1/2-EGR1 (early growth response 1) signaling cascade, through which HCC cells acquire a highly invasive ability via significantly enhanced filopodia formation. The inhibition of IMD blocks the phosphorylation of ERK1/2, resulting in EGR1 downregulation and endoplasmic reticulum stress (ER) stress, which is evidenced by the upregulation of ER stress marker DDIT3 (DNA damage-inducible transcript 3). The high level of DDIT3 induces HCC cells into an ER-stress related apoptotic pathway. Along with our previous finding that IMD plays critical roles in the vascular remodeling process that improves tumor blood perfusion, IMD may facilitate the acquisition of increased invasive abilities and a survival benefit by HCC cells, and it is easier for HCC cells to obtain blood supply via the vascular remodeling activities of IMD. According to these results, blockade of IMD activity may have therapeutic potential in the treatment of HCC.

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 Stiffer Matrix Accelerates Migration of Hepatocellular Carcinoma Cells through Enhanced Aerobic Glycolysis Via the MAPK-YAP Signaling

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 490 ◽  
Author(s):  
Qiu-Ping Liu ◽  
Qing Luo ◽  
Bin Deng ◽  
Yang Ju ◽  
Guan-Bin Song
Keyword(s):  
Hepatocellular Carcinoma ◽  
Extracellular Matrix ◽  
Cell Migration ◽  
Aerobic Glycolysis ◽  
Mapk Signaling ◽  
Carcinoma Cells ◽  
Metabolic Reprogramming ◽  
Signaling Cascade ◽  
And Migration ◽  
Hcc Cells

Increased extracellular matrix (ECM) stiffness and metabolic reprogramming of cancer cells are two fundamental mediators of tumor progression, including hepatocellular carcinoma (HCC). Yet, the correlation between ECM stiffness and excessive aerobic glycolysis in promoting the development of HCC remains unknown. Here, we demonstrated that stiffer ECM promotes HCC cell migration depending on their accelerated aerobic glycolysis. Our results also indicated that stiffer ECM-induced YAP activation plays a major role in promoting aerobic glycolysis of HCC cells. Moreover, we showed that JNK and p38 MAPK signaling are critical for mediating YAP activation in HCC cells. Together, our findings established that the MAPK-YAP signaling cascade that act as a mechanotransduction pathway is essential for promoting HCC cell aerobic glycolysis and migration in response to ECM stiffness.

scholarly journals Correlation between p53 expression and hepatocellular carcinoma differentiation grade

2020 ◽  
Vol 55 (1) ◽  
pp. 28-31
Author(s):  
B. K. Issamatov ◽  
E. A. Yenin ◽  
U. Sh. Medeubekov ◽  
B. B. Baymakhanov
Keyword(s):  
Hepatocellular Carcinoma ◽  
P53 Gene ◽  
Expression Level ◽  
Simultaneous Increase ◽  
Malignant Neoplasms ◽  
P53 Expression ◽  
Liver Cancers ◽  
Well Differentiated ◽  
High Level ◽  
Hcc Cells

Relevance: Hepatocellular carcinoma (HCC) is one of the world’s most common liver cancers and fatal malignant neoplasms. According to GLOBOCAN 2018, liver cancer ranks sixth in incidence (842,000 new cases) and fourth in mortality (782,000 deaths) globally. In Kazakhstan, there is an increase in HCC incidence from 879 cases in 2016 up to 984 cases in 2017, which amounted to 5.5 cases per 100 000 population. In 2017, the five-year survival rate was 23.7%. The mutations in the p53 gene that encodes the p53 protein are most frequent in HCC (35.2%). A high level of nuclear expression of p53 and a decrease in apoptosis of tumor cells with a simultaneous increase in their proliferative activity, noted in HCC cells, are important for the prognosis of the disease. There is a correlation between poor prognosis, a decreased survival of patients with HCC, and high expression of the p53 oncoprotein in HCC. U. Nzeako et al. have revealed a strong correlation of HCC histological differentiation with the patient survival rate. Therefore, a study of the correlation between p53 expression and HCC differentiation grade is very relevant. The purpose of this study was to analyze the correlation between p53 expression and HCC differentiation grade. Results: p53 was overexpressed in 18% of HCC cases; the expression was high in 62% and low in 20% of HCC cases. In well-differentiated HCC (G1), the p53-immunopositive nuclei expression was low in 10 cases and high in 2 cases. In moderately differentiated HCC (G2), p53 was highly expressed in 21 cases and overexpressed in 2 cases. In low-differentiated HCC (G3), p53 was overexpressed in 7 cases and highly expressed in 8 cases of HCC. The analysis of the correlation between p53 expression and HCC differentiation grade by Spearman showed a high correlation (r=0.79, p<0.01), evidencing a direct dependence of p53 expression level on HCC gradation. Conclusion: HCC differentiation grade highly correlates with p53 expression level in immunopositive nuclei of HCC cells. The obtained data evidences a dependence between p53 expression level and HCC gradation.

Hepatitis B virus small envelope protein promotes HCC angiogenesis via ER stress signaling to upregulate VEGFA expression

2021 ◽  
Author(s):  
Shu-Xiang Wu ◽  
Shuang-Shuang Ye ◽  
Yu-Xiang Hong ◽  
Yan Chen ◽  
Biao Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Endoplasmic Reticulum ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Er Stress ◽  
Viral Protein ◽  
Unfolded Protein ◽  
B Virus ◽  
Protein Response ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is a hypervascular tumor and accumulating evidence has indicated that stimulation of angiogenesis by HBV may contribute to HCC malignancy. The small protein of hepatitis B virus surface antigen (HBsAg), SHBs, is the most abundant HBV viral protein and has a close clinical association with HCC, however, whether SHBs contributes to HCC angiogenesis remains unknown. This study reports that forced expression of SHBs in HCC cells promoted xenograft tumor growth and increased the microvessel density (MVD) within the tumors. Consistently, HBsAg was also positively correlated with MVD count in HCC patients’ specimens. The conditioned media from the SHBs-transfected HCC cells increased the capillary tube formation and migration of human umbilical vein endothelial cells (HUVECs). Intriguingly, overexpression of SHBs increased VEGFA expression at both mRNA and protein levels. A higher VEGFA expression level was also observed in the xenograft tumors transplanted with SHBs-expressing HCC cells and in HBsAg-positive HCC tumor tissues as compared to their negative controls. As expected, in the culture supernatants, the secretion of VEGFA was also significantly enhanced from HCC cells expressing SHBs, which promoted HUVECs migration and vessel formation. Furthermore, all the three unfolded protein response (UPR) sensors IRE1α, PERK and ATF6 associated with endoplasmic reticulum (ER) stress were found activated in the SHBs-expressing cells and correlated with VEGFA protein expression and secretion. Taken together, these results suggest an important role of SHBs in HCC angiogenesis and may highlight a potential target for preventive and therapeutic intervention of HBV-related HCC and its malignant progression. IMPORTANCE Chronic hepatitis B virus infection is one of the important risk factors for the development and progression of hepatocellular carcinoma (HCC). HCC is characteristic of hypervascularization even at early phases of the disease due to overexpression of angiogenic factors like vascular endothelial growth factor-A (VEGFA). However, a detailed mechanism in the HBV-induced angiogenesis remains to be established. In this study, we demonstrate for the first time that the most abundant HBV viral protein, i.e. small surface antigens (SHBs) can enhance the angiogenic capacity of HCC cells by upregulation of VEGFA expression both in vitro and in vivo . Mechanistically, SHBs induced endoplasmic reticulum (ER) stress which consequently activated unfolded protein response (UPR) signaling to increase VEGFA expression and secretion. This study suggests that SHBs plays an important pro-angiogenic role in HBV-associated HCC and may represent a potential target for anti-angiogenic therapy in the HCC.

scholarly journals Inhibition of protein phosphatase 1 stimulates noncanonical ER stress eIF2α activation to enhance fisetin-induced chemosensitivity in HDAC inhibitor-resistant hepatocellular carcinoma cells

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 918 ◽  
Author(s):  
Liu ◽  
Yu-Chun ◽  
Chang ◽  
Kuo ◽  
Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Protein Phosphatase ◽  
Cell Apoptosis ◽  
Histone Deacetylase Inhibitors ◽  
Molecular Mechanisms ◽  
Chemotherapeutic Agents ◽  
Protein Phosphatase 1 ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is a common fatal type of malignant tumor that has highly metastatic and recurrent properties. Fisetin is a natural flavonoid found in various vegetables and fruits which exhibits anti-cancer and anti-inflammatory properties, as well as other effects. Thus, we hypothesized that fisetin can act as an adjuvant therapy in cancer or drug-resistant cancer cells, and further investigated the molecular mechanisms underlying the development of drug-resistance in HCC cells. We found that fisetin effectively inhibited the cell viability of not only parental cells but also histone deacetylase inhibitors-resistant (HDACis-R) cells and enhanced the chemosensitivity of HCC cells. Interestingly, fisetin did not induce cell apoptosis through the activation of the endoplasmic reticulum (ER) stress sensor of protein kinase R (PKR)-like endoplasmic reticulum kinase, but rather through the non-canonical pathway of the protein phosphatase 1 (PP1)-mediated suppression of eIF2α phosphorylation. Moreover, fisetin-induced cell apoptosis was reversed by treatment with PP1 activator or eIF2α siRNA in HCC cells. Based on these observations, we suggest that PP1-eIF2α pathways are significantly involved in the effect of fisetin on HCC apoptosis. Thus, fisetin may act as a novel anticancer drug and new chemotherapy adjuvant which can improve the efficacy of chemotherapeutic agents and diminish their side-effects.

scholarly journals Loss of MiR-192-5p Initiates a Hyperglycolysis and Stemness Positive Feedback in Hepatocellular Carcinoma.

2020 ◽  
Author(s):  
Yuanzhuo Gu ◽  
Fubo Ji ◽  
Niya Liu ◽  
Yongzhi Zhao ◽  
Xiyang Wei ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Line ◽  
Tumor Cells ◽  
Stellate Cell ◽  
Human Monocyte ◽  
Erk Phosphorylation ◽  
Tumor Tissues ◽  
Metabolic Properties ◽  
High Level ◽  
Hcc Cells

Abstract Background: Emerging studies revealed that cancer stem cells (CSCs) possessed peculiar metabolic properties, which however remained largely unknown in hepatocellular carcinoma (HCC). Genetic silencing of liver-abundant miR-192-5p was a key feature for multiple groups of CSC-positive HCCs. We thus aimed to investigate essential metabolic features of hepatic CSCs via using HCCs with miR-192-5p silencing as a model.Methods: Datasets from two independent HCC cohorts were used. Data integration analyses of miR-192-5p with metabolome and mRNA transcriptome data in HCC Cohort 1 were performed to investigate miR-192-5p related metabolic features, which was further validated in Cohort 2. Cellular and molecular assays were performed to examine whether and how miR-192-5p regulated the identified metabolic features. Co-culture systems consisting of HCC cells and LX2 (human hepatic stellate cell line) or THP1 (human monocyte cell line) were established to explore effects of the identified metabolic properties on stemness features of HCC cells via interacting with co-cultured non-tumor cells.Results: High levels of glycolysis-related metabolites and genes were present in HCCs with low miR-192-5p and CSC-positive HCCs in two independent HCC cohorts. miR-192-5p knockout cells displayed CSC features and miR-192-5p loss led to an enhanced glycolytic phenotype via upregulating three bona fide targets, GLUT1 and PFKFB3 (two glycolytic enzymes) and c-Myc (regulating glycolytic genes’ expression). Meanwhile, c-Myc suppressed miR-192-5p transcription, ensuring a low-miR-192-5p/high-c-Myc loop to maintain hyperglycolysis. Moreover, over-produced lactic acid from hyperglycolytic HCC cells stimulated the ERK phosphorylation of co-cultured LX2 and THP1 non-tumor cells partially via NDRG3 and MCT1, which in turn promoted cell malignancy and stemness of HCC cells. Consistently, HCC patients with low level of miR-192-5p in their tumor tissues and high level of NDRG3 or MCT1 in their non-tumor tissues had the shortest overall survival.Conclusions: In CSC-positive HCCs, miR-192-5p loss enhanced glycolysis and over produced lactate might further increase HCC malignant features via interacting with environmental non-tumor cells.

Kinesin family member 2C promotes hepatocellular carcinoma growth and metastasis via activating MEK/ERK pathway

2021 ◽  
Author(s):  
Qian Ding ◽  
Caihua Jiang ◽  
Yajing Zhou ◽  
Jianping Duan ◽  
Jianming Lai ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Family Member ◽  
Poor Prognosis ◽  
Migration And Invasion ◽  
Erk Pathway ◽  
High Level ◽  
The Impact ◽  
Kinesin Family ◽  
Hcc Cells

ABSTRACT The current work was intended to explore the function and mechanism of Kinesin family member 2C (KIF2C) in hepatocellular carcinoma (HCC). In this study, KIF2C expression was at a high level in HCC and indicated poor prognosis. Silencing KIF2C significantly suppressed the proliferation, migration and invasion in HCC cells. Furthermore, silencing KIF2C markedly decreased the expression of Snail, Vimentin, p-MEK and p-ERK, but increased E-cadherin expression in HCC cells. Moreover, we also found that MEK/ERK inhibitor U0126 could enhance the impact on cell proliferation, migration and invasion induced by silencing KIF2C in HCC. On the contrary, MEK/ERK activator PAF could weaken the impact induced by silencing KIF2C in HCC. Thus, our findings indicate that KIF2C can promote the proliferation, migration and invasion by activating MEK/ERK pathway in HCC.

mTor Targeting by Different Flavonoids for Cancer Prevention

2020 ◽  
Vol 27 ◽  
Author(s):  
Badar ul Islam ◽  
Mohd Shahnawaz Khan ◽  
Fohad Mabood Husain ◽  
Md Tabish Rehman ◽  
Torki A. Alzughaibi ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cell Survival ◽  
Anticancer Activity ◽  
Scientific Literature ◽  
Therapeutic Potential ◽  
Protein Kinase B ◽  
Mammalian Target Of Rapamycin ◽  
Akt Signaling ◽  
Signaling Cascade ◽  
The Past

: Over the past several decades, plant-derived products (phytochemicals) have been suggested to possess immense therapeutic potential. Among these phytochemicals, different flavonoids have been reported for their potent anticancer activity. To exhibit their anticancer potential, these flavonoids modulate different signaling pathways. Among these pathways, the mammalian target of rapamycin (mTOR) and associated phosphatidyl-inositiol 3-kinase (PI3K)/protein kinase B (Akt) signaling cascade has been suggested as a pivotal modulator of cell survival, proliferation, and death/apoptosis. Hence, targeting this cascade could be an ideal strategy to alleviate apoptosis and inhibit proliferation in different forms of cancer. The targeting of PI3K/Akt/mTOR by flavonoids have been well documented in the scientific literature. In the current communication, we have covered the anticancer potential of various flavonoids especially flavones, flavanols, and isoflavones that include apigenin, luteolin, biacalein, tangeretin, epigallocatechin-3-gallate, genistein, and diadzein especially dealing with mTOR targeting.

Isovitexin Inhibits Stemness and Induces Apoptosis in Hepatocellular Carcinoma SK-Hep-1 Spheroids by Upregulating miR-34a Expression

2020 ◽  
Vol 20 (14) ◽  
pp. 1654-1663 ◽  
Author(s):  
Chang Xu ◽  
Xiaocheng Cao ◽  
XiaoZheng Cao ◽  
Lihua Liu ◽  
Yebei Qiu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Therapeutic Potential ◽  
Cooperative Effect ◽  
Mrna Levels ◽  
Concomitant Increase ◽  
Apoptosis Resistance ◽  
Protein Levels ◽  
Bax Protein ◽  
Related Proteins ◽  
Hcc Cells

Background: We previously demonstrated that isovitexin (apigenin-6-C-glucoside, ISOV) suppressed the stemness of human Hepatocellular Carcinoma (HCC) cells. However, the mechanism of its action remains to be deciphered. Objective: The current study was to examine whether ISOV regulates the miR-34a expression and hence suppresses the stemness of HCC SK-Hep-1 cells. Methods: After identification of the stemness, apoptosis resistance and decreased miR-34a expression of spheres from SK-Hep-1 cells (SK-SC), we utilized transfection of a miR-34a mimic or inhibitor to investigate the effects of ISOV on miR-34a, Bcl-2, Bax and Mcl-1 expression in order to understand the mechanism underlying ISOV-mediated repression of stemness and promotion of apoptosis. Results: Our results demonstrated that SK-SC displayed higher stemness and resistance to apoptosis, as well as reduced miR-34a levels compared to SK-Hep-1 cells. ISOV suppressed sphere and colony formation, and decreased CD44+ cell populations. In addition, ABCG2, ALDH1, and NANOG mRNA levels were decreased, while there was a concomitant increase in miR-34a levels. With regards to apoptosis-related proteins, ISOV increased Bax protein levels, and reduced Bcl-2 and Mcl-1 protein levels in SK-SC. Importantly, there was a cooperative effect when miR-34a was overexpressed in the presence of ISOV in SK-SC, and down-regulation of miR-34a attenuated the effects of ISOV in SK-Hep-1 cells. Conclusion: We suggest that ISOV-mediated miR-34a upregulation induces apoptosis and suppresses the stemness of SK-SC. Our data indicate that ISOV exhibits therapeutic potential for the treatment of HCC.

miR-221/222 suppression protects against endoplasmic reticulum stress-induced apoptosis via p27Kip1- and MEK/ERK-mediated cell cycle regulation

2010 ◽  
Vol 391 (7) ◽  
Author(s):  
Rongyang Dai ◽  
Juan Li ◽  
Youping Liu ◽  
Dongmei Yan ◽  
Shaokun Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Cell Cycle Regulation ◽  
Underlying Mechanisms ◽  
Induced Apoptosis ◽  
Apoptosis Regulation ◽  
Cycle Regulation ◽  
Hcc Cells

Abstract Cancer cells are relatively resistant to endoplasmic reticulum (ER) stress-induced apoptosis. However, the underlying mechanisms remain largely unclear. We observed that the microRNAs miR-221/222 are associated with apoptosis regulation under ER stress in human hepatocellular carcinoma (HCC) cells. Induction of ER stress does not trigger significant apoptosis but obviously causes downregulation of miR-221/222 in HCC cells. In these cells, ER stress-induced apoptosis is enhanced by miR-221/222 mimics and attenuated by miR-221/222 inhibitors. miR-221/222 promoted-apoptosis under ER stress is associated with p27Kip1- and MEK/ERK-mediated cell cycle regulation. Our results suggest that suppression of miR-221/222 plays a crucial role in the protection against apoptosis induced by ER stress in HCC cells.

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