scholarly journals The Role of Fibrosis and Liver-Associated Fibroblasts in the Pathogenesis of Hepatocellular Carcinoma

2019 ◽  
Vol 20 (7) ◽  
pp. 1723 ◽  
Author(s):  
Jacopo Baglieri ◽  
David Brenner ◽  
Tatiana Kisseleva
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Associated Fibroblasts ◽  
Hepatic Inflammation ◽  
Therapeutic Approaches ◽  
Chronic Liver Injury ◽  
Mesenchymal Transition ◽  
Liver Fibrogenesis ◽  
Tumor Growth And Invasion

Hepatocellular carcinoma (HCC) is one of the most aggressive types of cancer and lacks effective therapeutic approaches. Most HCC develops in the setting of chronic liver injury, hepatic inflammation, and fibrosis. Hepatic stellate cells (HSCs) and cancer-associated fibroblasts (CAFs) are key players in liver fibrogenesis and hepatocarcinogenesis, respectively. CAFs, which probably derive from HSCs, activate into extracellular matrix (ECM)-producing myofibroblasts and crosstalk with cancer cells to affect tumor growth and invasion. In this review, we describe the different components which form the HCC premalignant microenvironment (PME) and the tumor microenvironment (TME), focusing on the liver fibrosis process and the biology of CAFs. We will describe the CAF-dependent mechanisms which have been suggested to promote hepatocarcinogenesis, such as the alteration of ECM, CAF-dependent production of cytokines and angiogenic factors, CAF-dependent reduction of immuno-surveillance, and CAF-dependent promotion of epithelial-mesenchymal transition (EMT). New knowledge of the fibrosis process and the role of CAFs in HCC may pave the way for new therapeutic strategies for liver cancer.

scholarly journals MYC-targeted WDR4 promotes proliferation, metastasis, and sorafenib resistance by inducing CCNB1 translation in hepatocellular carcinoma

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Peng Xia ◽  
Hao Zhang ◽  
Kequan Xu ◽  
Xiang Jiang ◽  
Meng Gao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
P53 Protein ◽  
Rna Modifications ◽  
M Cell ◽  
Mesenchymal Transition ◽  
Akt Phosphorylation ◽  
Repeat Domain ◽  
Cell Cycle Transition

AbstractHepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. However, there still remains a lack of effective diagnostic and therapeutic targets for this disease. Increasing evidence demonstrates that RNA modifications play an important role in the progression of HCC, but the role of the N7-methylguanosine (m7G) methylation modification in HCC has not been properly evaluated. Thus, the goal of the present study was to investigate the function and mechanism of the m7G methyltransferase WD repeat domain 4 (WDR4) in HCC as well as its clinical relevance and potential value. We first verified the high expression of WDR4 in HCC and observed that upregulated WDR4 expression increased the m7G methylation level in HCC. WDR4 promoted HCC cell proliferation by inducing the G2/M cell cycle transition and inhibiting apoptosis in addition to enhancing metastasis and sorafenib resistance through epithelial-mesenchymal transition (EMT). Furthermore, we observed that c-MYC (MYC) can activate WDR4 transcription and that WDR4 promotes CCNB1 mRNA stability and translation to enhance HCC progression. Mechanistically, we determined that WDR4 enhances CCNB1 translation by promoting the binding of EIF2A to CCNB1 mRNA. Furthermore, CCNB1 was observed to promote PI3K and AKT phosphorylation in HCC and reduce P53 protein expression by promoting P53 ubiquitination. In summary, we elucidated the MYC/WDR4/CCNB1 signalling pathway and its impact on PI3K/AKT and P53. Furthermore, the result showed that the m7G methyltransferase WDR4 is a tumour promoter in the development and progression of HCC and may act as a candidate therapeutic target in HCC treatment.

scholarly journals Role of NELF‑B in supporting epithelial‑mesenchymal transition and cell proliferation during hepatocellular carcinoma progression

2021 ◽  
Vol 22 (5) ◽  
Author(s):  
Mennatallah Ghouraba ◽  
Razan Masad ◽  
Eric Mpingirika ◽  
Omnia Abdelraheem ◽  
Rached Zeghlache ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition

scholarly journals RETRACTED ARTICLE: Sorcin Predicts Poor Prognosis and Promotes Metastasis by Facilitating Epithelial-mesenchymal Transition in Hepatocellular Carcinoma

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Xiong Lei ◽  
Yahang Liang ◽  
Jian Chen ◽  
Shuai Xiao ◽  
Jian Lei ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Poor Prognosis ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Significant Risk ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Multiple Tumor ◽  
Liver Tissues

Abstract Metastasis-associated recurrence is the main cause for the poor prognosis of hepatocellular carcinoma (HCC). However, the detailed molecular mechanisms underlying HCC metastasis remain elusive. Though some data indicated the oncogenic role of Sorcin in tumors, the prognostic value and biological role of Sorcin in HCC is still unknown. In this study, it demonstrated that Sorcin expression levels were significantly upregulated in HCC tumor tissues compared with matched adjacent nontumorous liver tissues and normal liver tissues, and such expression level correlated with HCC metastasis. High Sorcin expression was significantly correlated with aggressive clinicopathological characteristics such as multiple tumor nodules, high Edmondson-Steiner grade, microvascular invasion, advanced TNM stage and advanced BCLC stage (all P < 0.05). HCC patients with high Sorcin expression had both shorter survival and higher recurrence than those with low Sorcin expression (all P < 0.05). Sorcin expression was an independent and significant risk factor for survival and recurrence of HCC patients. Results of functional experiments showed that Sorcin could promote HCC cell proliferation, migration, and invasion in vitro, and facilitate HCC growth and metastasis in vivo. Mechanistically, Sorcin exerted its role by activating extracellular signal-regulated kinase (ERK) pathway and promoted metastasis by facilitating epithelial-mesenchymal transition (EMT) in HCC.

scholarly journals Knockdown of SLC34A2 Inhibits Hepatocellular Carcinoma Cell Proliferation and Invasion

2016 ◽  
Vol 24 (6) ◽  
pp. 511-519 ◽  
Author(s):  
Yanhua Li ◽  
Xia Chen ◽  
Hong Lu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Epithelial Mesenchymal Transition ◽  
Underlying Mechanism ◽  
Mesenchymal Transition ◽  
Human Carcinomas ◽  
And Migration ◽  
Proliferation And Invasion ◽  
Hcc Cells

The gene solute carrier family 34 (sodium phosphate), member 2 (SLC34A2), is a member of the SLC34 family. Increasing evidence suggests that SLC34A2 is involved in the development of many human carcinomas. However, its role in hepatocellular carcinoma (HCC) is still unclear. Therefore, in this study we investigated the role of SLC34A2 in HCC and explored the underlying mechanism. We found that the expression of SLC34A2 is upregulated in HCC cell lines. Knockdown of SLC34A2 obviously inhibited HCC cell proliferation, migration/invasion, and the epithelial‐mesenchymal transition (EMT) phenotype. Furthermore, knockdown of SLC34A2 significantly inhibited the expression of phosphorylated PI3K and AKT in HCC cells. Taken together, these results suggest that knockdown of SLC34A2 inhibits proliferation and migration by suppressing activation of the PI3K/AKT signaling pathway in HCC cells, and SLC34A2 may be a potential therapeutic target for the treatment of HCC.

scholarly journals Lineage Plasticity in Cancer: The Tale of a Skin-walker

2021 ◽  
Author(s):  
Archana P. Thankamony ◽  
Ayalur Raghu Subbalakshmi ◽  
Mohit Kumar Jolly ◽  
Radhika Nair
Keyword(s):  
Tumor Progression ◽  
Tissue Repair ◽  
Epithelial Mesenchymal Transition ◽  
Therapy Resistance ◽  
Therapeutic Resistance ◽  
Therapeutic Approaches ◽  
Mesenchymal Transition ◽  
Lineage Switch ◽  
Lymphoid Lineage

Lineage plasticity, the switching of cells from one lineage to another has been recognized to be a cardinal property essential for embryonic development, tissue repair and homeostasis. However, such a highly regulated process goes awry when cancer cells exploit this inherent ability to their advantage, resulting in tumorigenesis, relapse, metastasis and therapy resistance. In this review, we summarize our current understanding on the role of lineage plasticity in tumor progression and therapeutic resistance in multiple cancers. Lineage plasticity can be triggered by treatment itself and is reported across various solid as well as liquid tumors. Here we focus on the importance of lineage switching in tumor progression and therapeutic resistance of solid tumors such as the prostate, lung, hepatocellular and colorectal carcinoma and the myeloid and lymphoid lineage switch observed in leukemias. Besides this, we also discuss the role of Epithelial-Mesenchymal Transition (EMT) in facilitating the lineage switch in biphasic cancers such as aggressive carcinosarcomas. We also discuss the mechanisms involved, current therapeutic approaches and challenges that lie ahead in taming the scourge of lineage plasticity in cancer.

scholarly journals Secretomes of Primary Cancer-associated Fibroblasts Upregulate the Expression of Stemness Markers in HT-29 Human Colorectal Carcinoma Cells

2020 ◽  
Vol 12 (4) ◽  
pp. 333-339
Author(s):  
Septelia Inawati Wanandi ◽  
Dwi Retna Lestari ◽  
Noza Hilbertina ◽  
Nurjati Chairani Siregar ◽  
Sri Widia Jusman ◽  
...  
Keyword(s):  
Colorectal Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Stroma ◽  
Cancer Associated Fibroblasts ◽  
Trypan Blue Exclusion ◽  
Mesenchymal Transition ◽  
Cancer Associated Fibroblast ◽  
And Control ◽  
Ht 29

BACKGROUND: Cancer-associated fibroblast (CAF) is the most abundant tumor stroma. Our previous study has demonstrated that the secretomes of CAF isolated from colorectal carcinoma (CRC) patients could induce epithelial-mesenchymal transition in the HT-29 CRC cell line. However, the role of CAF secretomes in CRC stemness is needed to be further investigated. Therefore, the present study aimed to investigate the effect of CAF secretomes from CRC patients on the expression of stemness markers in HT-29 CRC cells in comparison with the secretomes from normal fibroblasts.METHODS: Fibroblasts were isolated from tumor (CAF) and their counterpart non-tumor (NF) areas of three CRC patients undergone surgical resection. Normal preputium fibroblasts (PF) were isolated during circumcision of three healthy boys aged 8 years. All fibroblasts were grown in free-serum culture medium for 24 hours to collect 50% (v/v) conditioned medium (CM). Then, CM was supplemented to HT-29 CRC cells for 72 hours. The effects of CAF- and NF-CM on the mRNA expression of CD44, CD133, OCT4, and ALDH1A1 were analysed using qRT-PCR. Cells proliferation was measured using the trypan blue exclusion assay.RESULTS: Supplementation of CAF-CM (50% v/v) significantly increased CD44, CD133, OCT4, and ALDH1A1 mRNA expressions compared to that of NF-CM and control without supplementation but had no effect on the proliferation of HT-29 cells.CONCLUSION: CAF secretomes from CRC patients upregulate the expression of CRC stemness.KEYWORDS: cancer-associated fibroblasts, ALDH1A1, OCT4, CD44, CD133, colorectal carcinoma

Downregulation of long noncoding RNA T1NCR inhibits cell proliferation, invasion, and epithelial-mesenchymal transition of hepatocellular carcinoma

2021 ◽  
Vol 7 (6) ◽  
pp. 6499-6510
Author(s):  
Hongjuan Li ◽  
Yaqin Chen ◽  
Chunyan Wu ◽  
Haiyan Zhao ◽  
Xuesong Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Noncoding Rna ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Normal Tissues ◽  
Proliferation Ability ◽  
Non Coding Rnas

Accumulating reports have identified that long non-coding RNAs (IncRNAs) function as key regulators of tumor initiation and progression. The aim of the current study was to determine the clinical significance and functional role of TINCR in hepatocellular carcinoma (HCC). In the present study, the level of IncRNA TINCR expression was significantly upregulated in HCC tissues compared to adjacent normal tissues. Higher levels of IncRNA TINCR expression were significantly correlated with tumor size and vascular invasion of HCC patients. LncRNA TINCR knockdown inhibited cell proliferation ability, increased the proportion of G1 phase cells, reduced the proportion of S phase cells, and suppressed cell invasion of HCC in vitro. Additionally, IncRNA TINCR knockdown inhibited the HCC cell epithelial-mesenchymal transition (EMT) phenomenon by upregulating E-cadherin and reducing N-cadherin expression. We demonstrated that knockdown of IncRNA reduced tumor growth in vivo. Thus, these results indicated that IncRNA TINCR exhibits a tumor oncogenic role in HCC and inhibition of IncRNA TINCR might serve as a therapeutic target for HCC.

scholarly journals High Expression of MicroRNA-196a is Associated with Progression of Hepatocellular Carcinoma in Younger Patients

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1549 ◽  
Author(s):  
Shen-Yung Wang ◽  
Chih-Li Chen ◽  
Yu-Chen Hu ◽  
Yi Chi ◽  
Yen-Hua Huang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
High Expression ◽  
Down Regulation ◽  
Younger Patients ◽  
Mesenchymal Transition ◽  
Sox2 Expression

MicroRNAs are small RNAs involved in various biological processes and cancer metastasis. miR-196a was associated with aggressive behaviors in several cancers. The role of miR-196a in hepatocellular carcinoma (HCC) metastasis remains unknown. This study aimed to examine the role of miR-196a in HCC progression. Expression of miR-196a was measured in 83 human HCC samples. The HCC patients with high miR-196a expression had younger ages, lower albumin levels, higher frequency with alpha-fetoprotein (AFP) levels ≥20 ng/mL, more macrovascular invasion, and non-early stages. Kaplan–Meier analysis showed that high miR-196a expression was associated with lower recurrence-free survival. Knockdown of miR-196a decreased transwell invasiveness, sphere formation, transendothelial invasion, and Slug, Twist, Oct4, and Sox2 expression, suppressed angiogenesis, and reduced sizes of xenotransplants and number of pulmonary metastasis. Down-regulation of miR-196a decreased Runx2 and osteopontin (OPN) levels. Knockdown of Runx2 in vitro resulted in comparable phenotypes with miR-196a down-regulation. Restoration of Runx2 in miR-196a-knockdown HCC reverted tumor phenotypes. This study showed that high expression of miR-196a is associated with HCC progression in a subset of younger patients. miR-196a mediates HCC progression via upregulation of Runx2, OPN, epithelial–mesenchymal transition (EMT) regulators, and stemness genes. We proposed that miR-196a can be used as a prognostic marker and a potential therapeutic target.

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