|
1
|
Doi S, Yasuda S, Nagai M, Nakamura K, Matsuo Y, Terai T, Kohara Y, Sakata T, Tanaka T, Minamiguchi K, Tachiiri T, Kunichika H, Ozu N, Sho M. Quantitative evaluation of tumor signal heterogeneity on gadoxetic acid-enhanced magnetic resonance imaging as a predictor of postoperative survival and antitumor immunity in hepatocellular carcinoma. Hepatol Res 2025. [PMID: 40376966 DOI: 10.1111/hepr.14204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2025] [Revised: 04/24/2025] [Accepted: 05/02/2025] [Indexed: 05/18/2025]
Abstract
AIM We investigated the efficacy of quantitative evaluation of tumor signal heterogeneity on gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) to predict prognosis and antitumor immunity in patients with hepatocellular carcinoma (HCC) undergoing liver resection. METHODS A total of 297 patients who underwent curative resection for primary HCC were included. Tumor signal heterogeneity in the hepatobiliary phase (HBP) of EOB-MRI was quantified as the coefficient of variation (CV), calculated as the standard deviation divided by the mean signal intensity. Patients were classified into homogeneous (low CV) and heterogeneous (high CV) groups based on a cutoff value of 0.16 from receiver operating characteristic curve analysis. Tumor-infiltrating CD4+ and CD8+ T cells and PD-L1 expression were assayed by immunohistochemistry, and their associations with tumor signal heterogeneity were evaluated. RESULTS Among the 297 patients, 116 (39.1%) were classified into the heterogeneous group. The overall survival (OS) and recurrence-free survival (RFS) rates were significantly lower in the heterogeneous group (p < 0.001 for both). Multivariate analysis identified heterogeneous group as an independent prognostic factor for OS and RFS (p < 0.001 and p = 0.012, respectively). Extrahepatic recurrence was significantly more frequent in the heterogeneous group (18.1% vs. 7.7%, p = 0.024). CD4+ and CD8+ T cells were significantly decreased, and the PD-L1 positivity rate was significantly lower in the heterogeneous group (p < 0.001 for all). CONCLUSIONS The quantitative evaluation of tumor signal heterogeneity in the HBP of EOB-MRI using CV is useful for predicting postoperative prognosis in patients with HCC. Tumor signal heterogeneity may also reflect impaired local immunity and an immunologically "cold" tumor.
Collapse
Affiliation(s)
- Shunsuke Doi
- Department of Surgery, Nara Medical University, Kashihara, Nara, Japan
| | - Satoshi Yasuda
- Department of Surgery, Nara Medical University, Kashihara, Nara, Japan
| | - Minako Nagai
- Department of Surgery, Nara Medical University, Kashihara, Nara, Japan
| | - Kota Nakamura
- Department of Surgery, Nara Medical University, Kashihara, Nara, Japan
| | - Yasuko Matsuo
- Department of Surgery, Nara Medical University, Kashihara, Nara, Japan
| | - Taichi Terai
- Department of Surgery, Nara Medical University, Kashihara, Nara, Japan
| | - Yuichiro Kohara
- Department of Surgery, Nara Medical University, Kashihara, Nara, Japan
| | - Takeshi Sakata
- Department of Surgery, Nara Medical University, Kashihara, Nara, Japan
| | - Toshihiro Tanaka
- Department of Diagnostic and Interventional Radiology, Nara Medical University, Kashihara, Nara, Japan
| | - Kiyoyuki Minamiguchi
- Department of Diagnostic and Interventional Radiology, Nara Medical University, Kashihara, Nara, Japan
| | - Tetsuya Tachiiri
- Department of Diagnostic and Interventional Radiology, Nara Medical University, Kashihara, Nara, Japan
| | - Hideki Kunichika
- Department of Diagnostic and Interventional Radiology, Nara Medical University, Kashihara, Nara, Japan
| | - Naoki Ozu
- Institute of Clinical and Translational Science, Nara Medical University Hospital, Kashihara, Nara, Japan
| | - Masayuki Sho
- Department of Surgery, Nara Medical University, Kashihara, Nara, Japan
| |
Collapse
|
|
2
|
Elfiky A, El-Guendy N, Badr AM, Mohammed MA, Wahab AHAA. The role of FOXA1 and miR-212-3p in molecular modulation of doxorubicin resistance in liver cancer. Med Oncol 2025; 42:160. [PMID: 40216647 PMCID: PMC11991990 DOI: 10.1007/s12032-025-02686-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Accepted: 03/11/2025] [Indexed: 04/14/2025]
Abstract
TACE (Transarterial Chemoembolization) is an essential current treatment for liver cancer. Resistance to doxorubicin, the chemotherapeutic component of TACE, poses a serious problem in this treatment, necessitating a deeper understanding of the underlying resistance mechanisms. Upregulation of the Forkhead box A1 transcription regulator in our model of doxorubicin-resistant liver cancer cell line suggested a role in resistance. To better understand the role of FOXA1 in resistance to doxorubicin, we inhibited its expression using siRNA or its miRNA-212-3p inhibitor then studied the effect on the cancer cell lines survival using SRB assay. The expression of several downstream epithelial-mesenchymal transition genes, namely SLUG, TWIST, CDH1 (E-Cadherin), was determined using quantitative real-time PCR. Our results showed a significant upregulation of FOXA1 and downregulation of miRNA-212-3p in doxorubicin-resistant cells. Manipulation of FOXA1 and miRNA-212-3p expressions restored sensitive cell characteristics. In addition, inhibition of FOXA1 increased apoptosis induction in resistant cells. Changes detected in the tested EMT genes point to progression toward more aggressive behavior in the doxorubicin-resistant liver cancer cell line that was reversed with inhibition of FOXA1. Our results suggest a possible role of FOXA1 and miRNA-212-3p in the development of resistance to chemotherapeutic drugs in liver cancer and the possibility of their use as prognostic and/or therapeutic targets.
Collapse
Affiliation(s)
- Ammar Elfiky
- Medical Biochemistry and Molecular Biology at Cancer Biology Department National Cancer Institute, Cairo University, Giza, Egypt
| | - Nadia El-Guendy
- Medical Biochemistry and Molecular Biology at Cancer Biology Department National Cancer Institute, Cairo University, Giza, Egypt
| | - Abeer Mahmoud Badr
- Zoology Department, Faculty of Science, Cairo University, Giza, 12613, Egypt
| | - Mohammed Aly Mohammed
- Medical Biochemistry and Molecular Biology at Cancer Biology Department National Cancer Institute, Cairo University, Giza, Egypt
| | - Abdel Hady A Abdel Wahab
- Medical Biochemistry and Molecular Biology at Cancer Biology Department National Cancer Institute, Cairo University, Giza, Egypt.
| |
Collapse
|
|
3
|
TOPCU GGÜNGÖR, AYSAN A, DİK Ş, ŞEKER M, BAHÇEKAPILI MB, TOPKARAOĞLU S, YAVUZER D, YAĞCI T. Knockdown of Plexin C1 induces epithelial-to-mesenchymal transition and confers resistance to multikinase inhibitors in hepatocellular carcinoma cells. Turk J Biol 2025; 49:219-232. [PMID: 40365104 PMCID: PMC12068671 DOI: 10.55730/1300-0152.2739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 04/25/2025] [Accepted: 01/08/2025] [Indexed: 05/15/2025] Open
Abstract
Background/aim HCC is a common and lethal malignancy and multi-kinase inhibitors (MKIs) are among the therapeutic options for unresectable cases. However, response rates to MKIs remained variable, necessitating the identification of predictive biomarkers. Plexin C1 (PLXNC1), a receptor involved in cell signaling, has emerged as a potential candidate to regulate tumor responses. This study aims to evaluate the impact of PLXNC1 expression on the sensitivity of HCC cells to MKI therapy. Materials and methods shRNA-mediated PLXNC1 knock-down and control clones of HCC cell lines PLC/PRF/5 and Hep3B were generated, and downregulation of PLXNC1 was confirmed using Western blotting. The effects of MKIs sorafenib and lenvatinib on apoptotic cell death and proliferation of HCC cell clones were explored in relation to PLXNC1 expression. Furthermore, tumor responses to MKIs were evaluated in mouse xenograft models engrafted with shPLXNC1 and control clones of PLC/PRF/5 cells. Results The results of our in vitro studies indicate that PLXNC1 expression is linked to heightened sensitivity of HCC cells to MKIs. Furthermore, the knockdown of PLXNC1 in these cells resulted in a reduction in proliferation and an increase in apoptosis resistance. The findings were validated in hepatocellular carcinoma (HCC) tumor models in immunodeficient mice, which revealed that cells expressing PLXNC1 were responsive to drug treatment. In PLXNC1-silenced cells, tumor volumes remained stationary, which was attributable to the antiproliferative effect of PLXNC1 knockdown. Conclusion PLXNC1 expression may serve as a predictive biomarker for MKI efficacy in HCC and provides a potential avenue for personalized therapeutic strategies. Further clinical validation is required to incorporate PLXNC1 into routine diagnostic and treatment protocols for HCC.
Collapse
Affiliation(s)
- Gamze GÜNGÖR TOPCU
- Department of Molecular Biology and Genetics, Faculty of Sciences, Gebze Technical University, Kocaeli,
Turkiye
- Central Research Laboratory (GTU-MAR), Gebze Technical University, Kocaeli,
Turkiye
| | - Arzu AYSAN
- Department of Molecular Biology and Genetics, Faculty of Sciences, Gebze Technical University, Kocaeli,
Turkiye
- Central Research Laboratory (GTU-MAR), Gebze Technical University, Kocaeli,
Turkiye
| | - Şevval DİK
- Department of Molecular Biology and Genetics, Faculty of Sciences, Gebze Technical University, Kocaeli,
Turkiye
- Central Research Laboratory (GTU-MAR), Gebze Technical University, Kocaeli,
Turkiye
| | - Maide ŞEKER
- Department of Molecular Biology and Genetics, Faculty of Sciences, Gebze Technical University, Kocaeli,
Turkiye
- Central Research Laboratory (GTU-MAR), Gebze Technical University, Kocaeli,
Turkiye
| | - Melike Binnur BAHÇEKAPILI
- Department of Molecular Biology and Genetics, Faculty of Sciences, Gebze Technical University, Kocaeli,
Turkiye
- Central Research Laboratory (GTU-MAR), Gebze Technical University, Kocaeli,
Turkiye
| | - Sude TOPKARAOĞLU
- Department of Histology and Embryology, Hamidiye Faculty of Medicine, University of Health Sciences, İstanbul,
Turkiye
| | - Dilek YAVUZER
- Department of Pathology, Hamidiye Faculty of Medicine, University of Health Sciences, Sancaktepe Şehit Prof. Dr. Ilhan Varank Training and Research Hospital, İstanbul,
Turkiye
| | - Tamer YAĞCI
- Department of Molecular Biology and Genetics, Faculty of Sciences, Gebze Technical University, Kocaeli,
Turkiye
- Central Research Laboratory (GTU-MAR), Gebze Technical University, Kocaeli,
Turkiye
| |
Collapse
|
|
4
|
Roy N, Lodh R, Mandal S, Kumar Jolly M, Sarma A, Bhattacharyya DK, Barah P. Comparative transcriptomic analysis uncovers molecular heterogeneity in hepatobiliary cancers. Transl Oncol 2025; 51:102192. [PMID: 39546955 PMCID: PMC11613176 DOI: 10.1016/j.tranon.2024.102192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 08/25/2024] [Accepted: 11/05/2024] [Indexed: 11/17/2024] Open
Abstract
Hepatobiliary cancers (HBCs) pose a major global health challenge, with a lack of effective targeted biomarkers. Due to their complex anatomical locations, shared risk factors, and the limitations of targeted therapies, generalized treatment strategies are often used for gallbladder cancer (GBC), hepatocellular carcinoma (HCC), and intrahepatic cholangiocarcinoma (ICC). This study aimed to identify specific transcriptomic signatures in GBC, HCC, and ICC. The transcriptomic data analysis revealed distinct expression profiles, highlighting complex molecular heterogeneity within these cancers, even within the same organ system. Functional annotation revealed distinct biological pathways associated with each type of HBCs. GBC was linked to cell cycle regulation, HCC was associated with immune system modulation, and ICC was involved in metabolic dysregulation, particularly lipid metabolism. Gene co-expression network (GCN) and protein-protein interaction (PPI) network analyses identified potential key genes, such as MAPK3 and ERBB2 in GBC, AC069287.1 and ACTN2 in HCC, and TRPC1 and BACE1 in ICC. The FOX family of transcription factors (TFs) was conserved across all three cancer types. To further explore the relationship between Epithelial-Mesenchymal Transition (EMT) and the identified hub genes and TFs, an EMT score analysis was conducted. This analysis revealed distinct phenotypic characteristics in each cancer type, with TFs identified in GBC and ICC showing a stronger correlation with EMT compared to those in HCC. External validation using The Cancer Genome Atlas (TCGA) databases confirmed the expression of candidate genes, underscoring their potential as therapeutic targets. These findings provide valuable insights into the molecular heterogeneity and complexity of HBCs, opening new avenues for personalized therapeutic interventions.
Collapse
Affiliation(s)
- Nabanita Roy
- Department of Molecular Biology and Biotechnology, Tezpur University, Napaam, Sonitpur, Assam, 784028, India
| | - Ria Lodh
- Department of Molecular Biology and Biotechnology, Tezpur University, Napaam, Sonitpur, Assam, 784028, India
| | - Susmita Mandal
- Department of Bioengineering, Indian Institute of Science, Bangalore 560012, India
| | - Mohit Kumar Jolly
- Department of Bioengineering, Indian Institute of Science, Bangalore 560012, India
| | - Anupam Sarma
- Department of Onco-pathology, Dr. Bhubaneswar Borooah Cancer Institute, Guwahati, Assam, 781016, India
| | - Dhruba Kumar Bhattacharyya
- Department of Computer Science and Engineering, Tezpur University, Napaam, Sonitpur, Assam, 784028, India
| | - Pankaj Barah
- Department of Molecular Biology and Biotechnology, Tezpur University, Napaam, Sonitpur, Assam, 784028, India.
| |
Collapse
|
|
5
|
Li J, Zhou Z, Zhang J, Wang M, Luan X, Zhao M, Jiang G, Wang G, Li S, Xiang W, Chen L, Zhou J. TUBB2B regulates epithelial-mesenchymal transition via interaction with Vimentin to promote glioma migration and invasion. Cancer Cell Int 2024; 24:423. [PMID: 39707368 DOI: 10.1186/s12935-024-03618-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 12/13/2024] [Indexed: 12/23/2024] Open
Abstract
BACKGROUND Epithelial-mesenchymal transition (EMT) plays a crucial role in the migration and invasion capabilities of glioblastoma (GBM) cells. Several studies have established tubulin as a significant regulator of the EMT process. Tubulin beta 2B class IIb (TUBB2B), a critical component of microtubules, has been linked to the prognosis of various tumors. However, the specific biological function and mechanism of TUBB2B in GBM remain unclear. METHODS In vitro experiments demonstrated that TUBB2B knockdown inhibited the migration and invasion of GBM cells, while its overexpression enhanced these capabilities. Western blot, immunofluorescence (IF) and co-immunoprecipitation (Co-IP) assays revealed that TUBB2B interacts with Vimentin. Molecular docking and residue mutation scanning indicated that TUBB2B interacts with Vimentin at the R391/K392/A393/F394 sites. In vivo experiments using nude mice confirmed that TUBB2B knockdown inhibited GBM cell invasion and migration. RESULTS TUBB2B was upregulated in GBM tissue samples compared with normal tissues. The sites of TUBB2B(R391/K392/A393/F394) physically interacts with Vimentin to induce EMT, which promotes migration and invasion. CONCLUSION TUBB2B may regulate EMT and promote the migration and invasion of GBM cells through its interaction with Vimentin, highlighting TUBB2B as a potential therapeutic target for GBM.
Collapse
Affiliation(s)
- Junxi Li
- Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, 25 Taiping Street, Luzhou, Sichuan, 646000, China
- Department of Neurosurgery, Yibin No.4 People's Hospital, Yibin, Sichuan, China
| | - Zhengjun Zhou
- Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, 25 Taiping Street, Luzhou, Sichuan, 646000, China
| | - Junrong Zhang
- Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, 25 Taiping Street, Luzhou, Sichuan, 646000, China
- Department of Neurosurgery, Suining First People's Hospital, Suining, Sichuan, China
| | - Ming Wang
- Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, 25 Taiping Street, Luzhou, Sichuan, 646000, China
| | - Xingzhao Luan
- Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, 25 Taiping Street, Luzhou, Sichuan, 646000, China
| | - Mingkuan Zhao
- Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, 25 Taiping Street, Luzhou, Sichuan, 646000, China
| | - Geng Jiang
- Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, 25 Taiping Street, Luzhou, Sichuan, 646000, China
| | - Guiyuan Wang
- Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, 25 Taiping Street, Luzhou, Sichuan, 646000, China
| | - Shenjie Li
- Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, 25 Taiping Street, Luzhou, Sichuan, 646000, China
| | - Wei Xiang
- Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, 25 Taiping Street, Luzhou, Sichuan, 646000, China.
- Sichuan Clinical Research Center for Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China.
- Academician (Expert) Workstation of Sichuan Province, Luzhou, Sichuan, China.
- Neurological Diseases and Brain Function Laboratory, Luzhou, Sichuan, China.
| | - Ligang Chen
- Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, 25 Taiping Street, Luzhou, Sichuan, 646000, China.
- Sichuan Clinical Research Center for Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China.
- Academician (Expert) Workstation of Sichuan Province, Luzhou, Sichuan, China.
- Neurological Diseases and Brain Function Laboratory, Luzhou, Sichuan, China.
| | - Jie Zhou
- Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, 25 Taiping Street, Luzhou, Sichuan, 646000, China.
- Sichuan Clinical Research Center for Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China.
- Academician (Expert) Workstation of Sichuan Province, Luzhou, Sichuan, China.
- Neurological Diseases and Brain Function Laboratory, Luzhou, Sichuan, China.
| |
Collapse
|
|
6
|
Ghionescu AV, Sorop A, Linioudaki E, Coman C, Savu L, Fogarasi M, Lixandru D, Dima SO. A predicted epithelial-to-mesenchymal transition-associated mRNA/miRNA axis contributes to the progression of diabetic liver disease. Sci Rep 2024; 14:27678. [PMID: 39532948 PMCID: PMC11557572 DOI: 10.1038/s41598-024-77416-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
Despite public health measures, type 2 diabetes (T2D) is still a significant concern worldwide, given its associated complications, including hepatic alterations. The role of epithelial-to-mesenchymal transition (EMT) in liver fibrosis is well established. However, its effects on the progression of diabetic liver diseases are not well understood. Therefore, this study aims to investigate the mRNA/miRNA axes involved in this process. Bioinformatic analysis revealed new EMT-associated genes (CDH2, ITGB1, COL4A1, COL1A1, TNC, CCN2, and JUN), which showed higher expression in obese T2D and hepatocellular carcinoma (HCC) patients. In addition, six miRNAs (miR-21-5p, miR-26a-5p, miR-34a-5p, miR-106a-5p, miR-320a-3p and miR-424-5p) have been found as potential targets. Among them, miR-26a-5p and miR-424-5p were significantly downregulated in nonalcoholic steatohepatitis (NASH) and HCC (p < 0.05), being considered potential negative regulators of the EMT process. In our hepatic mesenchymal culture model, miR-26a-5p negatively regulated cadherin 2 (also known as N-cadherin, CDH2) and promoted the cadherin 1 (also known as E-cadherin, CDH1) expression. Our results reveal potential molecules involved in liver tumor development. Moreover, we observe that miR-26a-5p impairs EMT in the initial stages of diabetic liver disease by inhibiting CDH2 and could be a valuable target in this pathology.
Collapse
Grants
- 629PED/2022 CCCDI-UEFISCDI, project number PN-III-P2-2.1-PED-2021-3180, within PNCDI III
- 629PED/2022 CCCDI-UEFISCDI, project number PN-III-P2-2.1-PED-2021-3180, within PNCDI III
- 629PED/2022 CCCDI-UEFISCDI, project number PN-III-P2-2.1-PED-2021-3180, within PNCDI III
- 629PED/2022 CCCDI-UEFISCDI, project number PN-III-P2-2.1-PED-2021-3180, within PNCDI III
- 629PED/2022 CCCDI-UEFISCDI, project number PN-III-P2-2.1-PED-2021-3180, within PNCDI III
- 629PED/2022 CCCDI-UEFISCDI, project number PN-III-P2-2.1-PED-2021-3180, within PNCDI III
- 629PED/2022 CCCDI-UEFISCDI, project number PN-III-P2-2.1-PED-2021-3180, within PNCDI III
- 28571/02.10.2023 UMFCD
Collapse
Affiliation(s)
- Alina-Veronica Ghionescu
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
- Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - Andrei Sorop
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
- University of Medicine and Pharmacy "Carol Davila", Bucharest, Romania
| | - Ekaterini Linioudaki
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
| | - Cristin Coman
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
- "Cantacuzino" National Medico-Military Institute for Research and Development, Bucharest, Romania
| | - Lorand Savu
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
| | - Marton Fogarasi
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
| | - Daniela Lixandru
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania.
- University of Medicine and Pharmacy "Carol Davila", Bucharest, Romania.
| | - Simona Olimpia Dima
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
- University of Medicine and Pharmacy "Carol Davila", Bucharest, Romania
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, Bucharest, Romania
| |
Collapse
|
|
7
|
Panettieri E, Campisi A, De Rose AM, Mele C, Giuliante F, Vauthey JN, Ardito F. Emerging Prognostic Markers in Patients Undergoing Liver Resection for Hepatocellular Carcinoma: A Narrative Review. Cancers (Basel) 2024; 16:2183. [PMID: 38927889 PMCID: PMC11201456 DOI: 10.3390/cancers16122183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 05/27/2024] [Accepted: 05/27/2024] [Indexed: 06/28/2024] Open
Abstract
In patients with hepatocellular carcinoma (HCC), liver resection is potentially curative. Nevertheless, post-operative recurrence is common, occurring in up to 70% of patients. Factors traditionally recognized to predict recurrence and survival after liver resection for HCC include pathologic factors (i.e., microvascular and capsular invasion) and an increase in alpha-fetoprotein level. During the past decade, many new markers have been reported to correlate with prognosis after resection of HCC: liquid biopsy markers, gene signatures, inflammation markers, and other biomarkers, including PIVKA-II, immune checkpoint molecules, and proteins in urinary exosomes. However, not all of these new markers are readily available in clinical practice, and their reproducibility is unclear. Liquid biopsy is a powerful and established tool for predicting long-term outcomes after resection of HCC; the main limitation of liquid biopsy is represented by the cost related to its technical implementation. Numerous patterns of genetic expression capable of predicting survival after curative-intent hepatectomy for HCC have been identified, but published findings regarding these markers are heterogenous. Inflammation markers in the form of prognostic nutritional index and different blood cell ratios seem more easily reproducible and more affordable on a large scale than other emerging markers. To select the most effective treatment for patients with HCC, it is crucial that the scientific community validate new predictive markers for recurrence and survival after resection that are reliable and widely reproducible. More reports from Western countries are necessary to corroborate the evidence.
Collapse
Affiliation(s)
- Elena Panettieri
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Andrea Campisi
- Hepatobiliary Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (A.C.); (A.M.D.R.); (C.M.); (F.G.); (F.A.)
| | - Agostino M. De Rose
- Hepatobiliary Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (A.C.); (A.M.D.R.); (C.M.); (F.G.); (F.A.)
| | - Caterina Mele
- Hepatobiliary Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (A.C.); (A.M.D.R.); (C.M.); (F.G.); (F.A.)
| | - Felice Giuliante
- Hepatobiliary Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (A.C.); (A.M.D.R.); (C.M.); (F.G.); (F.A.)
| | - Jean-Nicolas Vauthey
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Francesco Ardito
- Hepatobiliary Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (A.C.); (A.M.D.R.); (C.M.); (F.G.); (F.A.)
| |
Collapse
|
|
8
|
Kapoor S, Kalmegh V, Kumar H, Mandoli A, Shard A. Rare diseases and pyruvate kinase M2: a promising therapeutic connection. Drug Discov Today 2024; 29:103949. [PMID: 38492882 DOI: 10.1016/j.drudis.2024.103949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 03/06/2024] [Accepted: 03/11/2024] [Indexed: 03/18/2024]
Abstract
Pyruvate kinase M2 (PKM2) is a key glycolytic enzyme that regulates proliferating cell metabolism. The role of PKM2 in common diseases has been well established, but its role in rare diseases (RDs) is less understood. Over the past few years, PKM2 has emerged as a crucial player in RDs, including, neoplastic, respiratory, metabolic, and neurological disorders. Herein, we summarize recent findings and developments highlighting PKM2 as an emerging key player in RDs. We also discuss the current status of PKM2 modulation in RDs with particular emphasis on preclinical and clinical studies in addition to current challenges in the field.
Collapse
Affiliation(s)
- Saumya Kapoor
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research Ahmedabad (NIPER-A), Gandhinagar, Gujarat, India
| | - Vaishnavi Kalmegh
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research Ahmedabad (NIPER-A), Gandhinagar, Gujarat, India
| | - Hemant Kumar
- Department of Pharmacology and Toxicology, NIPER-A, Gandhinagar, Gujarat, India.
| | - Amit Mandoli
- Department of Biotechnology, NIPER-A, Gandhinagar, Gujarat, India.
| | - Amit Shard
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research Ahmedabad (NIPER-A), Gandhinagar, Gujarat, India.
| |
Collapse
|
|
9
|
Papadakos SP, Chatzikalil E, Arvanitakis K, Vakadaris G, Stergiou IE, Koutsompina ML, Argyrou A, Lekakis V, Konstantinidis I, Germanidis G, Theocharis S. Understanding the Role of Connexins in Hepatocellular Carcinoma: Molecular and Prognostic Implications. Cancers (Basel) 2024; 16:1533. [PMID: 38672615 PMCID: PMC11048329 DOI: 10.3390/cancers16081533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 04/15/2024] [Accepted: 04/16/2024] [Indexed: 04/28/2024] Open
Abstract
Connexins, a family of tetraspan membrane proteins forming intercellular channels localized in gap junctions, play a pivotal role at the different stages of tumor progression presenting both pro- and anti-tumorigenic effects. Considering the potential role of connexins as tumor suppressors through multiple channel-independent mechanisms, their loss of expression may be associated with tumorigenic activity, while it is hypothesized that connexins favor the clonal expansion of tumor cells and promote cell migration, invasion, and proliferation, affecting metastasis and chemoresistance in some cases. Hepatocellular carcinoma (HCC), characterized by unfavorable prognosis and limited responsiveness to current therapeutic strategies, has been linked to gap junction proteins as tumorigenic factors with prognostic value. Notably, several members of connexins have emerged as promising markers for assessing the progression and aggressiveness of HCC, as well as the chemosensitivity and radiosensitivity of hepatocellular tumor cells. Our review sheds light on the multifaceted role of connexins in HCC pathogenesis, offering valuable insights on recent advances in determining their prognostic and therapeutic potential.
Collapse
Affiliation(s)
- Stavros P. Papadakos
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (S.P.P.); (E.C.)
| | - Elena Chatzikalil
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (S.P.P.); (E.C.)
| | - Konstantinos Arvanitakis
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (K.A.); (G.V.)
- Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Georgios Vakadaris
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (K.A.); (G.V.)
| | - Ioanna E. Stergiou
- Pathophysiology Department, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (I.E.S.); (M.-L.K.)
| | - Maria-Loukia Koutsompina
- Pathophysiology Department, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (I.E.S.); (M.-L.K.)
| | - Alexandra Argyrou
- Academic Department of Gastroenterology, Laikon General Hospital, Athens University Medical School, 11527 Athens, Greece; (A.A.); (V.L.)
| | - Vasileios Lekakis
- Academic Department of Gastroenterology, Laikon General Hospital, Athens University Medical School, 11527 Athens, Greece; (A.A.); (V.L.)
| | | | - Georgios Germanidis
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (K.A.); (G.V.)
- Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Stamatios Theocharis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (S.P.P.); (E.C.)
| |
Collapse
|
|
10
|
Yayan J, Franke KJ, Berger M, Windisch W, Rasche K. Adhesion, metastasis, and inhibition of cancer cells: a comprehensive review. Mol Biol Rep 2024; 51:165. [PMID: 38252369 PMCID: PMC10803487 DOI: 10.1007/s11033-023-08920-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 10/23/2023] [Indexed: 01/23/2024]
Abstract
This comprehensive review delves into cancer's complexity, focusing on adhesion, metastasis, and inhibition. It explores the pivotal role of these factors in disease progression and therapeutic strategies. This review covers cancer cell migration, invasion, and colonization of distant organs, emphasizing the significance of cell adhesion and the intricate metastasis process. Inhibition approaches targeting adhesion molecules, such as integrins and cadherins, are discussed. Overall, this review contributes significantly to advancing cancer research and developing targeted therapies, holding promise for improving patient outcomes worldwide. Exploring different inhibition strategies revealed promising therapeutic targets to alleviate adhesion and metastasis of cancer cells. The effectiveness of integrin-blocking antibodies, small molecule inhibitors targeting Focal adhesion kinase (FAK) and the Transforming Growth Factor β (TGF-β) pathway, and combination therapies underscores their potential to disrupt focal adhesions and control epithelial-mesenchymal transition processes. The identification of as FAK, Src, β-catenin and SMAD4 offers valuable starting points for further research and the development of targeted therapies. The complex interrelationships between adhesion and metastatic signaling networks will be relevant to the development of new treatment approaches.
Collapse
Affiliation(s)
- Josef Yayan
- Department of Internal Medicine, Division of Pulmonary, Allergy, and Sleep Medicine, Witten/Herdecke University, HELIOS Clinic Wuppertal, Heusnerstr. 40, 42283, Wuppertal, Germany.
| | - Karl-Josef Franke
- Department of Internal Medicine, Pulmonary Division, Internal Intensive Care Medicine, Infectiology, and Sleep Medicine, Märkische Clinics Health Holding Ltd, Clinic Lüdenscheid, Witten/Herdecke University, Lüdenscheid, Germany
| | - Melanie Berger
- Department of Pneumology, Cologne Merheim Hospital, Witten/Herdecke University, Cologne, Germany
| | - Wolfram Windisch
- Department of Pneumology, Cologne Merheim Hospital, Witten/Herdecke University, Cologne, Germany
| | - Kurt Rasche
- Department of Internal Medicine, Division of Pulmonary, Allergy, and Sleep Medicine, Witten/Herdecke University, HELIOS Clinic Wuppertal, Heusnerstr. 40, 42283, Wuppertal, Germany
| |
Collapse
|
|
11
|
Yüregir Y, Kaçaroğlu D, Yaylacı S. Regulation of Hepatocellular Carcinoma Epithelial-Mesenchymal Transition Mechanism and Targeted Therapeutic Approaches. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1450:93-102. [PMID: 37452258 DOI: 10.1007/5584_2023_781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/18/2023]
Abstract
Hepatocellular carcinoma (HCC) is a primary liver malignancy that accounts for the majority of liver cancer cases, with multiple risk factors including chronic hepatitis B and C infections, alcohol abuse, and non-alcoholic fatty liver disease (NAFLD). Despite advancements in diagnosis and treatment, the survival rate of patients with advanced HCC remains low, creating an urgent need for new therapeutic targets and strategies.One biological process crucial to HCC progression is the epithelial-mesenchymal transition (EMT). EMT is a process that enables epithelial cells to acquire mesenchymal properties, including motility and invasiveness, by losing their cell-cell adhesion. Various signaling pathways, including TGF-β, Wnt/β-catenin, and Notch, have been implicated in regulating EMT in HCC.To inhibit EMT, targeted therapeutic approaches have been developed, and preclinical studies suggest that the inhibition of the TGF-β, Wnt/β-catenin, and Notch signaling pathways is promising. TGF-β receptor inhibitors, Wnt/β-catenin pathway inhibitors, and gamma-secretase inhibitors have shown efficacy in preclinical studies by inhibiting EMT and reducing tumor growth in HCC models. However, further clinical studies are necessary to determine their effectiveness in human patients.In addition to these approaches, further research is needed to identify other novel therapeutic targets and develop new treatment strategies for HCC. This review emphasizes the critical role of EMT in HCC progression and highlights the potential of targeting the TGF-β, Wnt/β-catenin, and Notch signaling pathways to inhibit EMT and reduce tumor growth in HCC. Future studies and clinical trials are necessary to validate these therapeutic strategies and develop effective treatments for HCC.
Collapse
Affiliation(s)
- Yelda Yüregir
- Molecular Biology and Genetics Department, İhsan Doğramacı Bilkent University, Ankara, Turkey
| | - Demet Kaçaroğlu
- Faculty of Medicine, Medical Biology Department, Lokman Hekim University, Ankara, Turkey
| | - Seher Yaylacı
- Faculty of Medicine, Medical Biology Department, Lokman Hekim University, Ankara, Turkey.
| |
Collapse
|
|
12
|
Chen CT, Chen CF, Lin TY, Hua WJ, Hua K, Tsai CY, Hsu CH. Traditional Chinese medicine Kuan-Sin-Yin decoction inhibits cell mobility via downregulation of CCL2, CEACAM1 and PIK3R3 in hepatocellular carcinoma cells. JOURNAL OF ETHNOPHARMACOLOGY 2023; 317:116834. [PMID: 37355084 DOI: 10.1016/j.jep.2023.116834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/10/2023] [Accepted: 06/21/2023] [Indexed: 06/26/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Kuan-Sin-Yin (KSY) is a traditional Chinese medical decoction, designed based on the classic Si-Jun-Zi-Tang decoction and used clinically to improve the synergic effects of energy promotion, liver function and cancer related symptom and quality of life. However, the anti-hepatocellular carcinoma (HCC) function of KSY is unclear. AIM OF THE STUDY This study aimed to investigate the anti-mobility activity of KSY on HCC cells and elucidate its molecular mechanism. MATERIALS AND METHODS Two malignancy hepatocellular carcinoma cells, Mahlavu and SK-Hep-1, were used for the test of cell proliferation via alarm blue assay. The wound healing and Transwell assays were used to determine the anti-mobility activity of KSY in HCC cells. Cell morphology was analyzed via confocal microscopy. The genomic profile of KSY-treated HCC cells was analyzed by microarray. The potential signaling pathways and bio-functions of KSY-mediated genes were analyzed by ingenuity pathway analysis (IPA). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the messenger RNA (mRNA) level of indicated gene. RESULTS KSY did not affect cell viability of HCC cells but significantly inhibited cell migration and invasion in those HCC Mahlavu and SK-Hep-1 cells. In parallel, KSY induced changes in morphology of HCC cells via re-modulating actin cytoskeleton. KSY upregulated 1270 genes but reduced 1534 genes in Mahlavu cells. KSY regulated various gene networks which controlled cell migration, invasion and movement. Specifically, KSY reduced expression of chemokine (C-C motif) ligand 2 (CCL2), which is correlated to cell mobility, and concomitantly downregulated mRNA levels of phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3) and CEA cell adhesion molecule 1 (CEACAM1). CONCLUSION These findings indicated that regulation of CCL2-mediated PIK3R3 and CEACAM1 may be involved in KSY inhibited cell mobility. Moreover, KSY may be a potential a Chinese decoction for reducing cell mobility.
Collapse
Affiliation(s)
- Chueh-Tan Chen
- Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
| | - Chian-Feng Chen
- Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.
| | - Tung-Yi Lin
- Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Program in Molecular Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
| | - Wei-Jyun Hua
- Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Program in Molecular Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
| | - Kate Hua
- Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.
| | - Ching-Yao Tsai
- Department of Ophthalmology, Taipei City Hospital, Taipei, Taiwan; Institute of Public Health, National Yang Ming Chiao Tung University, Taipei, Taiwan; Department of Business Administration, Fu Jen Catholic University, New Taipei, Taiwan; General Education Center, University of Taipei, Taipei, Taiwan.
| | - Chung-Hua Hsu
- Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Department of Chinese Medicine, Taipei City Hospital, Linsen, Chinese Medicine, and Kunming Branch, Taipei, Taiwan.
| |
Collapse
|
|
13
|
Tseng TH, Shao YC, Lee YJ, Lee HJ. 2-(4-Benzyloxy-3-methoxyphenyl)-5-(carbethoxyethylene)-7-methoxy-benzofuran, a Benzofuran Derivative, Suppresses Metastasis Effects in P53-Mutant Hepatocellular Carcinoma Cells. Biomedicines 2023; 11:2027. [PMID: 37509669 PMCID: PMC10377018 DOI: 10.3390/biomedicines11072027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 07/10/2023] [Accepted: 07/16/2023] [Indexed: 07/30/2023] Open
Abstract
2-(4-Benzyloxy-3-methoxyphenyl)-5-(carbethoxyethylene)-7-methoxy-benzofuran (BMBF), a benzofuran derivative, is an intermediate found in the process of total synthesis of ailanthoidol. Benzofuran derivatives are a class of compounds that possess various biological and pharmacological activities. The present study explored the anti-metastasis effects of BMBF in hepatocellular carcinoma (HCC). Our preliminary findings indicate that BMBF suppresses the proliferation and changes the morphology of Huh7-an HCC cell line with a mutated p53 gene (Y220C). According to a scratching motility assay, non-cytotoxic concentrations of BMBF significantly inhibited the motility and migration in Huh7 cells. BMBF upregulated the expression of E-cadherin and downregulated the expression of vimentin, Slug, and MMP9, which are associated with epithelial-mesenchymal transition (EMT) and metastasis in Huh7 cells. BMBF decreased the expression of integrin α7, deactivated its downstream signal FAK/AKT, and inhibited p53 protein levels. Cell transfection with p53 siRNA resulted in the prevention of cell invasion because of the reduction in integrin α7, Slug, and MMP-9 in Huh7 cells. BMBF had anti-metastatic effects in PLC/PRF/5-an HCC cell line with R249S, a mutated p53 gene. Our findings indicate that BMBF has anti-metastatic effects in downregulating p53 and mediating the suppression of integrin α7, EMT, and MMP-9 in HCC cells with a mutated p53 gene.
Collapse
Affiliation(s)
- Tsui-Hwa Tseng
- Department of Medical Applied Chemistry, Chung Shan Medical University, Taichung 40201, Taiwan
- Department of Medical Education, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
| | - Yi-Chia Shao
- Department of Medical Applied Chemistry, Chung Shan Medical University, Taichung 40201, Taiwan
| | - Yean-Jang Lee
- Department of Chemistry, National Changhua University of Education, Changhua 50007, Taiwan
| | - Huei-Jane Lee
- Department of Biochemistry, School of Medicine, College of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
- Department of Clinical Laboratory, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
| |
Collapse
|
|
14
|
Cao J, Yang S, Luo T, Yang R, Zhu H, Zhao T, Jiang K, Xu B, Wang Y, Chen F. TATA-box-binding protein promotes hepatocellular carcinoma metastasis through epithelial-mesenchymal transition. Hepatol Commun 2023; 7:e00155. [PMID: 37314767 DOI: 10.1097/hc9.0000000000000155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 03/02/2023] [Indexed: 06/15/2023] Open
Abstract
BACKGROUND HCC characterizes malignant metastasis with high incidence and recurrence. Thus, it is pivotal to discover the mechanisms of HCC metastasis. TATA-box-binding protein (TBP), a general transcriptional factor (TF), couples with activators and chromatin remodelers to sustain the transcriptional activity of target genes. Here, we investigate the key role of TBP in HCC metastasis. METHODS TBP expression was measured by PCR, western blot, and immunohistochemistry. RNA-sequencing was performed to identify downstream proteins. Functional assays of TBP and downstream targets were identified in HCC cell lines and xenograft models. Luciferase reporter and chromatin immunoprecipitation assays were used to demonstrate the mechanism mediated by TBP. RESULTS HCC patients showed high expression of TBP, which correlated with poor prognosis. Upregulation of TBP increased HCC metastasis in vivo and in vitro, and muscleblind-like-3 (MBNL3) was the effective factor of TBP, positively related to TBP expression. Mechanically, TBP transactivated and enhanced MBNL3 expression to stimulate exon inclusion of lncRNA-paxillin (PXN)-alternative splicing (AS1) and, thus, activated epithelial-mesenchymal transition for HCC progression through upregulation of PXN. CONCLUSIONS Our data revealed that TBP upregulation is an HCC enhancer mechanism that increases PXN expression to drive epithelial-mesenchymal transition.
Collapse
Affiliation(s)
- Jiayi Cao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Shaanxi, Xi'an, China
| | - Suzhen Yang
- Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu, Nanjing, China
- Department of Gastroenterology and Hepatology, Jinling Hospital, Medical School of Nanjing University, Jiangsu, Nanjing, China
| | - Tingting Luo
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Shaanxi, Xi'an, China
| | - Rui Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Shaanxi, Xi'an, China
| | - Hanlong Zhu
- Department of Gastroenterology and Hepatology, Jinling Hospital, Medical School of Nanjing University, Jiangsu, Nanjing, China
| | - Tianming Zhao
- Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu, Nanjing, China
| | - Kang Jiang
- Department of Gastroenterology and Hepatology, Jinling Hospital, Medical School of Nanjing University, Jiangsu, Nanjing, China
| | - Bing Xu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Shaanxi, Xi'an, China
| | - Yingchun Wang
- Department of Gastroenterology, the Affiliated Zhongshan Hospital of Dalian University, Liaoning, Dalian, China
| | - Fulin Chen
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Shaanxi, Xi'an, China
| |
Collapse
|
|
15
|
Ji S, Xu M, Cai C, He X. MESP1-knockdown inhibits the proliferation and epithelial mesenchymal transition of hepatocellular carcinoma and enhances the tumor-suppressive effect of 5-fluorouracil. Biochem Biophys Res Commun 2023; 670:1-11. [PMID: 37271034 DOI: 10.1016/j.bbrc.2023.05.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/03/2023] [Accepted: 05/12/2023] [Indexed: 06/06/2023]
Abstract
Primary liver hepatocellular carcinoma (HCC) is the third most deadly malignancy worldwide,in part, because it is often diagnosed at an advanced stage. Thus, molecular markers are needed to aid in the early diagnosis and treatment of HCC. Expression of abnormal mesoderm posterior-1 (MESP1) promotes tumorigenesis; however,its role in the regulation of HCC proliferation, apoptosis,and invasion is unknown. Here,we analyzed data in The Cancer Genome Atlas (TCGA)and Genotype Tissue Expression (GTEx) databases on the pan-cancer expression of MESP1 and its relationship with clinical characteristics and prognosis of patients with HCC. The expression of MESP1 was measured in 48 HCC tissues using immunohistochemical staining,and the results were correlated with clinical stage, tumor differentiation, tumor size,and metastasis. MESP1 expression was downregulated using small interfering RNA (siRNA) in the HCC cell lines HepG2 and Hep3B,and cell viability, proliferation,cell cycle, apoptosis,and invasion were analyzed. Finally,we also evaluated the tumor suppression effect of MESP1 downregulation combined with 5-fluorouracil (5-FU) treatment. Our results showed that MESP1 is a pan-oncogene associated with poor prognosis in patients with HCC. siRNA-induced downregulation of MESP1 expression in HepG2 and Hep3B cells exhibited downregulation of β-catenin and GSK3β expression 48h after transfection, along with an increase in apoptosis rate, arrest in the G1-S phase,and a decrease in mitochondrial membrane potential. Moreover,the expression levels of c-Myc, PARP1, bcl2, Snail1, MMP9, and immune checkpoint genes (TIGIT, CTLA4,LAG3,CD274,and PDCD1) were downregulated, while those of caspase3 and E-cadherin were upregulated. Tumor cells also showed decreased migration ability. Furthermore, siRNA interference of MESP1 expression combined with 5-FU-treatment of HCC cells significantly enhanced the G1-S phase block and apoptosis. MESP1 showed an aberrant high expression in HCC and was associated with poor clinical outcomes; therefore, MESP1 may be a potential target for the diagnosis and treatment of HCC.
Collapse
Affiliation(s)
- Shuqin Ji
- Department of Pathology, Chongqing Medical University, 400016, China; Pathological Diagnosis Center of Chongqing Medical University, 400016, China
| | - Man Xu
- Department of Pathology, Chongqing Medical University, 400016, China; Pathological Diagnosis Center of Chongqing Medical University, 400016, China.
| | - Chenyu Cai
- Department of Pathology, Chongqing Medical University, 400016, China; Pathological Diagnosis Center of Chongqing Medical University, 400016, China
| | - Xinyue He
- Department of Pathology, Chongqing Medical University, 400016, China; Pathological Diagnosis Center of Chongqing Medical University, 400016, China
| |
Collapse
|
|
16
|
MicroRNA-483-5p Inhibits Hepatocellular Carcinoma Cell Proliferation, Cell Steatosis, and Fibrosis by Targeting PPARα and TIMP2. Cancers (Basel) 2023; 15:cancers15061715. [PMID: 36980601 PMCID: PMC10046356 DOI: 10.3390/cancers15061715] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/06/2023] [Accepted: 03/08/2023] [Indexed: 03/16/2023] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNA molecules that bind with the 3′ untranslated regions (UTRs) of genes to regulate expression. Downregulation of miR-483-5p (miR-483) is associated with the progression of hepatocellular carcinoma (HCC). However, the significant roles of miR-483 in nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver diseases (AFLD), and HCC remain elusive. In the current study, we investigated the biological significance of miR-483 in NAFLD, AFLD, and HCC in vitro and in vivo. The downregulation of miR-483 expression in HCC patients’ tumor samples was associated with Notch 3 upregulation. Overexpression of miR-483 in a human bipotent progenitor liver cell line HepaRG and HCC cells dysregulated Notch signaling, inhibited cell proliferation/migration, induced apoptosis, and increased sensitivity towards antineoplastic agents sorafenib/regorafenib. Interestingly, the inactivation of miR-483 upregulated cell steatosis and fibrosis signaling by modulation of lipogenic and fibrosis gene expression. Mechanistically, miR-483 targets PPARα and TIMP2 gene expression, which leads to the suppression of cell steatosis and fibrosis. The downregulation of miR-483 was observed in mice liver fed with a high-fat diet (HFD) or a standard Lieber-Decarli liquid diet containing 5% alcohol, leading to increased hepatic steatosis/fibrosis. Our data suggest that miR-483 inhibits cell steatosis and fibrogenic signaling and functions as a tumor suppressor in HCC. Therefore, miR-483 may be a novel therapeutic target for NAFLD/AFLD/HCC management in patients with fatty liver diseases and HCC.
Collapse
|
|
17
|
Minamiguchi K, Nishiofuku H, Saito N, Sato T, Taiji R, Matsumoto T, Maeda S, Chanoki Y, Tachiiri T, Kunichika H, Inoue T, Marugami N, Tanaka T. Quantitative Analysis of Signal Heterogeneity in the Hepatobiliary Phase of Pretreatment Gadoxetic Acid-Enhanced MRI as a Prognostic Imaging Biomarker in Transarterial Chemoembolization for Intermediate-Stage Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:cancers15041238. [PMID: 36831582 PMCID: PMC9954181 DOI: 10.3390/cancers15041238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 02/07/2023] [Accepted: 02/12/2023] [Indexed: 02/18/2023] Open
Abstract
BACKGROUND In the era of local and systemic therapies for intermediate-stage hepatocellular carcinoma (HCC), personalized therapy has become available. The aim of our study was to evaluate the usefulness of quantitative analysis of pretreatment gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) to predict prognosis following transarterial chemoembolization (TACE). METHODS This retrospective study included patients with treatment-naïve intermediate-stage HCC who underwent EOB-MRI before the initial TACE and were treated by initial TACE between February 2007 and January 2016. Signal heterogeneity in the hepatobiliary phase (HBP) of EOB-MRI was quantitatively evaluated by the coefficient of variation (CV). The cutoff CV value was determined using the Classification and Regression Tree algorithm. RESULTS A total of 64 patients were enrolled. In multivariate analysis, High CV (≥0.16) was significantly associated with poor prognosis (p = 0.038). In a subgroup analysis of patients within up-to-7 criteria, MST was significantly shorter in the High CV group than in the Low CV group (37.7 vs. 82.9 months, p = 0.024). In patients beyond up-to-7 criteria, MST was 18.0 and 38.3 months in the High CV and Low CV groups, respectively (p = 0.182). In both groups scanned at 1.5 T or 3.0 T, High CV was significantly associated with poor prognosis (p = 0.001 and 0.003, respectively). CONCLUSION CV of the tumor in the HBP of EOB-MRI is a valuable prognostic factor of TACE.
Collapse
Affiliation(s)
- Kiyoyuki Minamiguchi
- Department of Diagnostic and Interventional Radiology, Nara Medical University, Shijyocho 840, Kashihara City 634-8522, Japan
- Correspondence: ; Tel.:+81-744-22-3051
| | - Hideyuki Nishiofuku
- Department of Diagnostic and Interventional Radiology, Nara Medical University, Shijyocho 840, Kashihara City 634-8522, Japan
| | - Natsuhiko Saito
- Department of Diagnostic and Interventional Radiology, Nara Medical University, Shijyocho 840, Kashihara City 634-8522, Japan
| | - Takeshi Sato
- Department of Diagnostic and Interventional Radiology, Nara Medical University, Shijyocho 840, Kashihara City 634-8522, Japan
| | - Ryosuke Taiji
- Department of Diagnostic and Interventional Radiology, Nara Medical University, Shijyocho 840, Kashihara City 634-8522, Japan
| | - Takeshi Matsumoto
- Department of Diagnostic and Interventional Radiology, Nara Medical University, Shijyocho 840, Kashihara City 634-8522, Japan
| | - Shinsaku Maeda
- Department of Diagnostic and Interventional Radiology, Nara Medical University, Shijyocho 840, Kashihara City 634-8522, Japan
| | - Yuto Chanoki
- Department of Diagnostic and Interventional Radiology, Nara Medical University, Shijyocho 840, Kashihara City 634-8522, Japan
| | - Tetsuya Tachiiri
- Department of Diagnostic and Interventional Radiology, Nara Medical University, Shijyocho 840, Kashihara City 634-8522, Japan
| | - Hideki Kunichika
- Department of Diagnostic and Interventional Radiology, Nara Medical University, Shijyocho 840, Kashihara City 634-8522, Japan
| | - Takashi Inoue
- Department of Evidence-Based Medicine, Nara Medical University, Shijyocho 840, Kashihara City 634-8522, Japan
| | - Nagaaki Marugami
- Department of Diagnostic and Interventional Radiology, Nara Medical University, Shijyocho 840, Kashihara City 634-8522, Japan
| | - Toshihiro Tanaka
- Department of Diagnostic and Interventional Radiology, Nara Medical University, Shijyocho 840, Kashihara City 634-8522, Japan
| |
Collapse
|
|
18
|
Abdel Halim AS, Rudayni HA, Chaudhary AA, Ali MAM. MicroRNAs: Small molecules with big impacts in liver injury. J Cell Physiol 2023; 238:32-69. [PMID: 36317692 DOI: 10.1002/jcp.30908] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 09/30/2022] [Accepted: 10/14/2022] [Indexed: 11/07/2022]
Abstract
A type of small noncoding RNAs known as microRNAs (miRNAs) fine-tune gene expression posttranscriptionally by binding to certain messenger RNA targets. Numerous physiological processes in the liver, such as differentiation, proliferation, and apoptosis, are regulated by miRNAs. Additionally, there is growing evidence that miRNAs contribute to liver pathology. Extracellular vesicles like exosomes, which contain secreted miRNAs, may facilitate paracrine and endocrine communication between various tissues by changing the gene expression and function of distal cells. The use of stable miRNAs as noninvasive biomarkers was made possible by the discovery of these molecules in body fluids. Circulating miRNAs reflect the conditions of the liver that are abnormal and may serve as new biomarkers for the early detection, prognosis, and evaluation of liver pathological states. miRNAs are appealing therapeutic targets for a range of liver disease states because altered miRNA expression is associated with deregulation of the liver's metabolism, liver damage, liver fibrosis, and tumor formation. This review provides a comprehensive review and update on miRNAs biogenesis pathways and mechanisms of miRNA-mediated gene silencing. It also outlines how miRNAs affect hepatic cell proliferation, death, and regeneration as well as hepatic detoxification. Additionally, it highlights the diverse functions that miRNAs play in the onset and progression of various liver diseases, including nonalcoholic fatty liver disease, alcoholic liver disease, fibrosis, hepatitis C virus infection, and hepatocellular carcinoma. Further, it summarizes the diverse liver-specific miRNAs, illustrating the potential merits and possible caveats of their utilization as noninvasive biomarkers and appealing therapeutic targets for liver illnesses.
Collapse
Affiliation(s)
- Alyaa S Abdel Halim
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Hassan Ahmed Rudayni
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Anis Ahmad Chaudhary
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Mohamed A M Ali
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.,Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| |
Collapse
|
|
19
|
Xiang Y, Fan D, An Q, Zhang T, Wu X, Ding J, Xu X, Yue G, Tang S, Du Q, Xu J, Xie R. Effects of Ion-Transporting Proteins on the Digestive System Under Hypoxia. Front Physiol 2022; 13:870243. [PMID: 36187789 PMCID: PMC9515906 DOI: 10.3389/fphys.2022.870243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 06/13/2022] [Indexed: 11/13/2022] Open
Abstract
Hypoxia refers to a state of oxygen limitation, which mainly mediates pathological processes in the human body and participates in the regulation of normal physiological processes. In the hypoxic environment, the main regulator of human body homeostasis is the hypoxia-inducible factor family (HIF). HIF can regulate the expression of many hypoxia-induced genes and then participate in various physiological and pathological processes of the human body. Ion-transporting proteins are extremely important types of proteins. Ion-transporting proteins are distributed on cell membranes or organelles and strictly control the inflow or outflow of ions in cells or organelles. Changes in ions in cells are often closely related to extensive physiological and pathological processes in the human body. Numerous studies have confirmed that hypoxia and its regulatory factors can regulate the transcription and expression of ion-transporting protein-related genes. Under hypoxic stress, the regulation and interaction of ion-transporting proteins by hypoxia often leads to diseases of various human systems and even tumors. Using ion-transporting proteins and hypoxia as targets to explore the mechanism of digestive system diseases and targeted therapy is expected to become a new breakthrough point.
Collapse
Affiliation(s)
- Yiwei Xiang
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi, China
| | - Dongdong Fan
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi, China
| | - Qimin An
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi, China
| | - Ting Zhang
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi, China
| | - Xianli Wu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi, China
| | - Jianhong Ding
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi, China
| | - Xiaolin Xu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi, China
| | - Gengyu Yue
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi, China
| | - Siqi Tang
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi, China
| | - Qian Du
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi, China
| | - Jingyu Xu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi, China
- *Correspondence: Jingyu Xu, ; Rui Xie,
| | - Rui Xie
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi, China
- *Correspondence: Jingyu Xu, ; Rui Xie,
| |
Collapse
|
|
20
|
Miri-Lavasani Z, Torabi S, Solhi R, Shokouhian B, Afsharian P, Heydari Z, Piryaei A, Farzaneh Z, Hossein-khannazer N, Es HA, Zahmatkesh E, Nussler A, Hassan M, Najimi M, Vosough M. Conjugated Linoleic Acid Treatment Attenuates Cancerous features in Hepatocellular Carcinoma Cells. Stem Cells Int 2022; 2022:1850305. [PMID: 36132168 PMCID: PMC9484933 DOI: 10.1155/2022/1850305] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 07/15/2022] [Accepted: 08/01/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND A growing number of hepatocellular carcinoma (HCC), and recurrence frequency recently have drawn researchers' attention to alternative approaches. The concept of differentiation therapies (DT) relies on inducing differentiation in HCC cells in order to inhibit recurrence and metastasis. Hepatocyte nuclear factor 4 alpha (HNF4α) is the key hepatogenesis transcription factor and its upregulation may decrease the invasiveness of cancerous cells by suppressing epithelial-mesenchymal transition (EMT). This study aimed to evaluate the effect of conjugated linoleic acid (CLA) treatment, natural ligand of HNF4α, on the proliferation, migration, and invasion capacities of HCC cells in vitro. Materials and Method. Sk-Hep-1 and Hep-3B cells were treated with different doses of CLA or BIM5078 [1-(2'-chloro-5'-nitrobenzenesulfonyl)-2-methylbenzimidazole], an HNF4α antagonist. The expression levels of HNF4a and EMT related genes were evaluated and associated to hepatocytic functionalities, migration, and colony formation capacities, as well as to viability and proliferation rate of HCC cells. RESULTS In both HCC lines, CLA treatment induced HNF4α expression in parallel to significantly decreased EMT marker levels, migration, colony formation capacity, and proliferation rate, whereas BIM5078 treatment resulted in the opposite effects. Moreover, CLA supplementation also upregulated ALB, ZO1, and HNF4α proteins as well as glycogen storage capacity in the treated HCC cells. CONCLUSION CLA treatment can induce a remarkable hepatocytic differentiation in HCC cells and attenuates cancerous features. This could be as a result of HNF4a induction and EMT inhibition.
Collapse
Affiliation(s)
- Zohre Miri-Lavasani
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Shukoofeh Torabi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Applied Cell Sciences, Faculty of Basic Sciences and Advanced Medical Technologies, Royan Institute, Academic Center for Education, Culture and Research, Tehran, Iran
| | - Roya Solhi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Bahareh Shokouhian
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Parvaneh Afsharian
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Zahra Heydari
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Abbas Piryaei
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Farzaneh
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Nikoo Hossein-khannazer
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Ensieh Zahmatkesh
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Siegfried Weller Institute for Trauma Research, University of Tübingen, 72076 Tübingen, Germany
| | - Andreas Nussler
- Siegfried Weller Institute for Trauma Research, University of Tübingen, 72076 Tübingen, Germany
| | - Moustapha Hassan
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research, Université Catholique de Louvain, Brussels, Belgium
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| |
Collapse
|
|
21
|
Fekry B, Ribas-Latre A, Drunen RV, Santos RB, Shivshankar S, Dai Y, Zhao Z, Yoo SH, Chen Z, Sun K, Sladek FM, Younes M, Eckel-Mahan K. Hepatic circadian and differentiation factors control liver susceptibility for fatty liver disease and tumorigenesis. FASEB J 2022; 36:e22482. [PMID: 35947136 PMCID: PMC10062014 DOI: 10.1096/fj.202101398r] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 07/06/2022] [Accepted: 07/21/2022] [Indexed: 11/11/2022]
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths, and the most common primary liver malignancy to present in the clinic. With the exception of liver transplant, treatment options for advanced HCC are limited, but improved tumor stratification could open the door to new treatment options. Previously, we demonstrated that the circadian regulator Aryl Hydrocarbon-Like Receptor Like 1 (ARNTL, or Bmal1) and the liver-enriched nuclear factor 4 alpha (HNF4α) are robustly co-expressed in healthy liver but incompatible in the context of HCC. Faulty circadian expression of HNF4α- either by isoform switching, or loss of expression- results in an increased risk for HCC, while BMAL1 gain-of-function in HNF4α-positive HCC results in apoptosis and tumor regression. We hypothesize that the transcriptional programs of HNF4α and BMAL1 are antagonistic in liver disease and HCC. Here, we study this antagonism by generating a mouse model with inducible loss of hepatic HNF4α and BMAL1 expression. The results reveal that simultaneous loss of HNF4α and BMAL1 is protective against fatty liver and HCC in carcinogen-induced liver injury and in the "STAM" model of liver disease. Furthermore, our results suggest that targeting Bmal1 expression in the absence of HNF4α inhibits HCC growth and progression. Specifically, pharmacological suppression of Bmal1 in HNF4α-deficient, BMAL1-positive HCC with REV-ERB agonist SR9009 impairs tumor cell proliferation and migration in a REV-ERB-dependent manner, while having no effect on healthy hepatocytes. Collectively, our results suggest that stratification of HCC based on HNF4α and BMAL1 expression may provide a new perspective on HCC properties and potential targeted therapeutics.
Collapse
Affiliation(s)
- Baharan Fekry
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
| | - Aleix Ribas-Latre
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
| | - Rachel Van Drunen
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
| | - Rafael Bravo Santos
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
| | - Samay Shivshankar
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
| | - Yulin Dai
- Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center, Houston, Texas, USA
| | - Zhongming Zhao
- Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center, Houston, Texas, USA.,Human Genetics Center, School of Public Health, The University of Texas Health Science Center, Houston, Texas, USA
| | - Seung-Hee Yoo
- Department of Biochemistry and Molecular Biology, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
| | - Zheng Chen
- Department of Biochemistry and Molecular Biology, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
| | - Kai Sun
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA.,Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
| | - Frances M Sladek
- Department of Molecular, Cell and Systems Biology, University of California, Riverside, California, USA
| | - Mamoun Younes
- Department of Pathology, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA
| | - Kristin Eckel-Mahan
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA.,Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
| |
Collapse
|
|
22
|
Yoshinari K, Shizu R. Distinct Roles of the Sister Nuclear Receptors PXR and CAR in Liver Cancer Development. Drug Metab Dispos 2022; 50:1019-1026. [PMID: 35184041 DOI: 10.1124/dmd.121.000481] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 02/08/2022] [Indexed: 02/13/2025] Open
Abstract
Pregnane X receptor (PXR) and constitutively active receptor/constitutive androstane receptor (CAR) are xenobiotic-responsible transcription factors belonging to the same nuclear receptor gene subfamily and highly expressed in the liver. These receptors are activated by a variety of chemicals and play pivotal roles in many liver functions, including xenobiotic metabolism and disposition. Phenobarbital, an enzyme inducer and liver tumor promoter, activates both rodent and human CAR but causes liver tumors only in rodents. Although the precise mechanism for phenobarbital/CAR-mediated liver tumor formation remains to be established, intracellular pathways, including the Hippo pathway/Yes-associated protein-TEA-domain family members system and β-catenin signaling, seem to be involved. In contrast to CAR, previous findings by our group suggest that PXR activation does not promote hepatocyte proliferation but it enhances the proliferation induced by various stimuli. Moreover, and surprisingly, PXR may have antitumor effects in both rodents and humans by targeting inflammatory cytokine signals, angiogenesis and epithelial-mesenchymal transition. In this review, we summarize the current knowledge on the associations of PXR and CAR with hepatocyte proliferation and liver tumorigenesis and their molecular mechanisms and species differences. SIGNIFICANCE STATEMENT: Pregnane X receptor and constitutively active receptor/constitutive androstane receptor have very similar functions in the gene regulation associated with xenobiotic disposition, as suggested by their identification as xenosensors for enzyme induction. In contrast, recent reports clearly suggest that these receptors play distinct roles in the control of hepatocyte proliferation and liver cancer development. Understanding these differences at the molecular level may help us evaluate the human safety of chemical compounds and develop novel drugs targeting liver cancers.
Collapse
Affiliation(s)
- Kouichi Yoshinari
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Ryota Shizu
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| |
Collapse
|
|
23
|
Zanotti S, Boot GF, Coto-Llerena M, Gallon J, Hess GF, Soysal SD, Kollmar O, Ng CKY, Piscuoglio S. The Role of Chronic Liver Diseases in the Emergence and Recurrence of Hepatocellular Carcinoma: An Omics Perspective. Front Med (Lausanne) 2022; 9:888850. [PMID: 35814741 PMCID: PMC9263082 DOI: 10.3389/fmed.2022.888850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 05/23/2022] [Indexed: 12/02/2022] Open
Abstract
Hepatocellular carcinoma (HCC) typically develops from a background of cirrhosis resulting from chronic inflammation. This inflammation is frequently associated with chronic liver diseases (CLD). The advent of next generation sequencing has enabled extensive analyses of molecular aberrations in HCC. However, less attention has been directed to the chronically inflamed background of the liver, prior to HCC emergence and during recurrence following surgery. Hepatocytes within chronically inflamed liver tissues present highly activated inflammatory signaling pathways and accumulation of a complex mutational landscape. In this altered environment, cells may transform in a stepwise manner toward tumorigenesis. Similarly, the chronically inflamed environment which persists after resection may impact the timing of HCC recurrence. Advances in research are allowing an extensive epigenomic, transcriptomic and proteomic characterization of CLD which define the emergence of HCC or its recurrence. The amount of data generated will enable the understanding of oncogenic mechanisms in HCC from the CLD perspective and provide the possibility to identify robust biomarkers or novel therapeutic targets for the treatment of primary and recurrent HCC. Importantly, biomarkers defined by the analysis of CLD tissue may permit the early detection or prevention of HCC emergence and recurrence. In this review, we compile the current omics based evidence of the contribution of CLD tissues to the emergence and recurrence of HCC.
Collapse
Affiliation(s)
- Sofia Zanotti
- Anatomic Pathology Unit, IRCCS Humanitas University Research Hospital, Milan, Italy
| | - Gina F. Boot
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Mairene Coto-Llerena
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland
- Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - John Gallon
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Gabriel F. Hess
- Clarunis, University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Savas D. Soysal
- Clarunis, University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Otto Kollmar
- Clarunis, University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Charlotte K. Y. Ng
- Department for BioMedical Research, University of Bern, Bern, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
- Bern Center for Precision Medicine, Bern, Switzerland
| | - Salvatore Piscuoglio
- Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland
- Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
- *Correspondence: Salvatore Piscuoglio
| |
Collapse
|
|
24
|
The Synergistic Cooperation between TGF-β and Hypoxia in Cancer and Fibrosis. Biomolecules 2022; 12:biom12050635. [PMID: 35625561 PMCID: PMC9138354 DOI: 10.3390/biom12050635] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 03/10/2022] [Accepted: 04/14/2022] [Indexed: 12/24/2022] Open
Abstract
Transforming growth factor β (TGF-β) is a multifunctional cytokine regulating homeostasis and immune responses in adult animals and humans. Aberrant and overactive TGF-β signaling promotes cancer initiation and fibrosis through epithelial–mesenchymal transition (EMT), as well as the invasion and metastatic growth of cancer cells. TGF-β is a key factor that is active during hypoxic conditions in cancer and is thereby capable of contributing to angiogenesis in various types of cancer. Another potent role of TGF-β is suppressing immune responses in cancer patients. The strong tumor-promoting effects of TGF-β and its profibrotic effects make it a focus for the development of novel therapeutic strategies against cancer and fibrosis as well as an attractive drug target in combination with immune regulatory checkpoint inhibitors. TGF-β belongs to a family of cytokines that exert their function through signaling via serine/threonine kinase transmembrane receptors to intracellular Smad proteins via the canonical pathway and in combination with co-regulators such as the adaptor protein and E3 ubiquitin ligases TRAF4 and TRAF6 to promote non-canonical pathways. Finally, the outcome of gene transcription initiated by TGF-β is context-dependent and controlled by signals exerted by other growth factors such as EGF and Wnt. Here, we discuss the synergistic cooperation between TGF-β and hypoxia in development, fibrosis and cancer.
Collapse
|
|
25
|
Worlikar T, Zhang M, Ganguly A, Hall TL, Shi J, Zhao L, Lee FT, Mendiratta-Lala M, Cho CS, Xu Z. Impact of Histotripsy on Development of Intrahepatic Metastases in a Rodent Liver Tumor Model. Cancers (Basel) 2022; 14:1612. [PMID: 35406383 PMCID: PMC8996987 DOI: 10.3390/cancers14071612] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 03/18/2022] [Indexed: 02/04/2023] Open
Abstract
Histotripsy has been used for tumor ablation, through controlled, non-invasive acoustic cavitation. This is the first study to evaluate the impact of partial histotripsy ablation on immune infiltration, survival outcomes, and metastasis development, in an in vivo orthotopic, immunocompetent rat HCC model (McA-RH7777). At 7−9 days post-tumor inoculation, the tumor grew to 5−10 mm, and ~50−75% tumor volume was treated by ultrasound-guided histotripsy, by delivering 1−2 cycle histotripsy pulses at 100 Hz PRF (focal peak negative pressure P− >30 MPa), using a custom 1 MHz transducer. Complete local tumor regression was observed on MRI in 9/11 histotripsy-treated rats, with no local recurrence or metastasis up to the 12-week study end point, and only a <1 mm residual scar tissue observed on histology. In comparison, 100% of untreated control animals demonstrated local tumor progression, developed intrahepatic metastases, and were euthanized at 1−3 weeks. Survival outcomes in histotripsy-treated animals were significantly improved compared to controls (p-value < 0.0001). There was evidence of potentially epithelial-to-mesenchymal transition (EMT) in control tumor and tissue healing in histotripsy-treated tumors. At 2- and 7-days post-histotripsy, increased immune infiltration of CD11b+, CD8+ and NK cells was observed, as compared to controls, which may have contributed to the eventual regression of the untargeted tumor region in histotripsy-treated tumors.
Collapse
Affiliation(s)
- Tejaswi Worlikar
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA; (T.W.); (T.L.H.)
| | - Man Zhang
- Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA; (M.Z.); (M.M.-L.)
| | - Anutosh Ganguly
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA; (A.G.); (C.S.C.)
| | - Timothy L. Hall
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA; (T.W.); (T.L.H.)
| | - Jiaqi Shi
- Department of Pathology & Clinical Labs, Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA;
| | - Lili Zhao
- Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA;
| | - Fred T. Lee
- Department of Radiology, University of Wisconsin, Madison, WI 53705, USA;
| | - Mishal Mendiratta-Lala
- Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA; (M.Z.); (M.M.-L.)
| | - Clifford S. Cho
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA; (A.G.); (C.S.C.)
- Department of Surgery, Ann Arbor VA Healthcare, Ann Arbor, MI 48105, USA
| | - Zhen Xu
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA; (T.W.); (T.L.H.)
| |
Collapse
|
|
26
|
Quan G, Ren B, Xu J, Zhou J, Wu G, Li Q, Li J. Effect and Mechanism of LncRNA HOTAIR on Migration, Apoptosis and Proliferation of Hepatocellular Carcinoma Cells. J BIOMATER TISS ENG 2022. [DOI: 10.1166/jbt.2022.2894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
<sec> <title>Objective:</title> This study was designed to probe the influence and mechanism of lncRNA HOTAIR on migration, apoptosis and proliferation of hepatocellular carcinoma (HCC) cells. </sec> <sec> <title>Methods:</title>
We evaluated LncRNA HOTAIR expression in HCC tissues and adjacent tissues, and serum of HCC patients and healthy controls. Later, we knocked down lncRNA HOTAIR, and utilized CCK-8 to determine Hep3B cell proliferation, flow cytometry for prospecting Hep3B cell apoptosis, and cell scratch
assay for observing Hep3B cell migration.We anticipated the direct target of lncRNA HOTAIR, and adopted luciferase reporter assay to verify. Moreover, we inhibitedmiR-126-5p expression, and rescue experiment for evaluating the influence of si-HOTAIR+miR-126-5p inhibitors on Hep3B cell migration,
apoptosis as well as proliferation. </sec> <sec> <title>Results:</title> Our results showed that lncRNA HOTAIR expression in tumor tissues and serum was significantly increased. Moreover, lncRNA HOTAIR inhibition significantly decreased the Hep3B cell proliferation
rate, elevated Hep3B cell apoptosis rate, and inhibited Hep3B cell migration. Luciferase reporter assay suggested that miR-126-5p was the direct target of lncRNA HOTAIR. Furthermore, co-transfection of si-HOTAIR+miR-126-5p inhibitor could diminishthe effects of HOTAIR silencing on apoptosis,
proliferation and migration. </sec> <sec> <title>Conclusion:</title> Silencing of lncRNA-HOTAIR can inhibit the HCC cell migration and proliferation, and increase the apoptosis by up-regulating miR-126-5p expression. </sec>
Collapse
Affiliation(s)
- Gang Quan
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan Province, 637000, China
| | - Bo Ren
- Department of Ultrasound Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan Province, 637000, China
| | - Jian Xu
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan Province, 637000, China
| | - Jie Zhou
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan Province, 637000, China
| | - Guo Wu
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan Province, 637000, China
| | - Qiang Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan Province, 637000, China
| | - Jingdong Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan Province, 637000, China
| |
Collapse
|
|
27
|
Hepatitis B Viral Protein HBx and the Molecular Mechanisms Modulating the Hallmarks of Hepatocellular Carcinoma: A Comprehensive Review. Cells 2022; 11:cells11040741. [PMID: 35203390 PMCID: PMC8870387 DOI: 10.3390/cells11040741] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 02/10/2022] [Accepted: 02/16/2022] [Indexed: 02/06/2023] Open
Abstract
With 296 million cases estimated worldwide, chronic hepatitis B virus (HBV) infection is the most common risk factor for hepatocellular carcinoma (HCC). HBV-encoded oncogene X protein (HBx), a key multifunctional regulatory protein, drives viral replication and interferes with several cellular signalling pathways that drive virus-associated hepatocarcinogenesis. This review article provides a comprehensive overview of the role of HBx in modulating the various hallmarks of HCC by supporting tumour initiation, progression, invasion and metastasis. Understanding HBx-mediated dimensions of complexity in driving liver malignancies could provide the key to unlocking novel and repurposed combinatorial therapies to combat HCC.
Collapse
|
|
28
|
Fu Y, Ci H, Du W, Dong Q, Jia H. CHRNA5 Contributes to Hepatocellular Carcinoma Progression by Regulating YAP Activity. Pharmaceutics 2022; 14:275. [PMID: 35214008 PMCID: PMC8877699 DOI: 10.3390/pharmaceutics14020275] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/15/2022] [Accepted: 01/20/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a major health concern worldwide. A better understanding of the mechanisms underlying the malignant phenotype is necessary for developing novel therapeutic strategies for HCC. Signaling pathways initiated by neurotransmitter receptors, such as α5-nicotinic acetylcholine receptor (CHRNA5), have been reported to be implicated in tumor progression. However, the functional mechanism of CHRNA5 in HCC remains unclear. In this study, we explored the role of CHRNA5 in HCC and found that CHRNA5 expression was increased in human HCC tissues and positively correlated with the T stage (p < 0.05) and AJCC phase (p < 0.05). The KM plotter database showed that the high expression level of CHRNA5 was strongly associated with worse survival in HCC patients. Both in vitro and in vivo assays showed that CHRNA5 regulates the proliferation ability of HCC by regulating YAP activity. In addition, CHRNA5 promotes the stemness of HCC by regulating stemness-associated genes, such as Nanog, Sox2 and OCT4. Cell migration and invasion assays demonstrated that CHRNA5 significantly enhanced the metastasis of HCC by regulating epithelial-mesenchymal transition (EMT)-associated genes. Furthermore, we found that CHRNA5 regulates the sensitivity of sorafenib in HCC. Our findings suggest that CHRNA5 plays a key role in the progression and drug resistance of HCC, and targeting CHRNA5 may be a strategy for the treatment of HCC.
Collapse
Affiliation(s)
- Yan Fu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China; (Y.F.); (H.C.); (W.D.)
| | - Hongfei Ci
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China; (Y.F.); (H.C.); (W.D.)
| | - Wei Du
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China; (Y.F.); (H.C.); (W.D.)
| | - Qiongzhu Dong
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China; (Y.F.); (H.C.); (W.D.)
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer, Shanghai Municipal Health Commission (SMHC), Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai 200437, China
| | - Huliang Jia
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China; (Y.F.); (H.C.); (W.D.)
| |
Collapse
|
|
29
|
EMT and Inflammation: Crossroads in HCC. J Gastrointest Cancer 2022; 54:204-212. [PMID: 35020133 DOI: 10.1007/s12029-021-00801-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/29/2021] [Indexed: 10/19/2022]
Abstract
Hepatocellular carcinoma is one of the major causes of cancer-related deaths worldwide and is associated with several inflammatory mediators, since 90% of HCCs occur based on chronic hepatitis B or C, alcoholism or increasingly metabolic syndrome-associated inflammation. EMT is a physiological process, with coordinated changes in epithelial gene signatures and is regulated by multiple factors, including cytokines and growth factors such as TGFβ, EGF, and FGF. Recent reports propose a strong association between EMT and inflammation, which is also correlated with tumor aggressiveness and poor outcomes. Cellular heterogeneity results collectively as an outcome of EMT, inflammation, and the tumor microenvironment, and it plays a fundamental role in the progression, complexity of cancer, and chemoresistance. In this review, we highlight recent developments concerning the association of EMT and inflammation in the context of HCC progression. Identifying potential EMT-related biomarkers and understanding EMT regulatory molecules will likely contribute to promising developments in clinical practice and will be a valuable tool for predicting metastasis in general and specifically in HCC.
Collapse
|
|
30
|
Hu H, Zhang S, Xiong S, Hu B, He Y, Gu Y. ACTR3 promotes cell migration and invasion by inducing epithelial mesenchymal transition in pancreatic ductal adenocarcinoma. J Gastrointest Oncol 2021; 12:2325-2333. [PMID: 34790395 DOI: 10.21037/jgo-21-609] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 10/19/2021] [Indexed: 12/13/2022] Open
Abstract
Background Recurrence and metastasis are the major causes of pancreatic ductal adenocarcinoma (PDAC) mortality after treatment. The underlying molecular mechanism is poorly understood. Actin-related protein 3 (ACTR3) is an important component of the actin-related protein 2/3 complex, which is involved in the regulation of cell motility and epithelial mesenchymal transition (EMT) process. Previously published studies have indicated that ACTR3 expression is upregulated in several types of cancers, and promotes tumor development, including gastric cancer and hepatocellular carcinoma. However, to date, the expression levels and the role of ACTR3 in PDAC are not well understood. Methods In the present study, the expression levels of ACTR3 in PDAC tissue and the relationship of ACTR3 expression with clinical prognosis were analyzed by mRNA microarray and bioinformatics. The biological functions and underlying mechanism of ACTR3 in PDAC were examined by a series of assays, including Cell Counting Kit-8 (CCK-8), transwell assay, and Western blotting. Results We found that the expression of ACTR3 was significantly increased in PDAC tissues and cell lines. A higher expression of ACTR3 was predictive of poor outcome for patients with PDAC. In vitro, the knockdown of ACTR3 expression significantly inhibited the invasive and migratory capacity of PDAC cells, and altered the distribution of F-actin and the expression of EMT markers. Conclusions The findings of our study indicated that ACTR3 promotes cell migration and invasion by inducing EMT in PDAC, which may be a potential therapeutic target and prognostic indicator for PDAC patients.
Collapse
Affiliation(s)
- Hao Hu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China.,School of Medicine, Jiangnan University, Wuxi, China.,Department of Hepatobiliary and Pancreatic Surgery, The Third Hospital Affiliated to Nantong University, Wuxi, China.,School of Medicine, Nantong University, Nantong, China.,Wuxi Institute of Hepatobiliary Surgery, Wuxi, China
| | - Shuo Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China.,School of Medicine, Jiangnan University, Wuxi, China
| | - Shuming Xiong
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China.,School of Medicine, Jiangnan University, Wuxi, China
| | - Benshun Hu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China.,Wuxi Institute of Hepatobiliary Surgery, Wuxi, China
| | - Youzhao He
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China.,Wuxi Institute of Hepatobiliary Surgery, Wuxi, China
| | - Yuanlong Gu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China.,School of Medicine, Jiangnan University, Wuxi, China.,Wuxi Institute of Hepatobiliary Surgery, Wuxi, China
| |
Collapse
|
|
31
|
Carissimi F, Barbaglia MN, Salmi L, Ciulli C, Roccamatisi L, Cordaro G, Mallela VR, Minisini R, Leone BE, Donadon M, Torzilli G, Pirisi M, Romano F, Famularo S. Finding the seed of recurrence: Hepatocellular carcinoma circulating tumor cells and their potential to drive the surgical treatment. World J Gastrointest Surg 2021; 13:967-978. [PMID: 34621473 PMCID: PMC8462072 DOI: 10.4240/wjgs.v13.i9.967] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/25/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
The treatment for hepatocellular carcinoma (HCC) relies on liver resection, which is, however, burdened by a high rate of recurrence after surgery, up to 60% at 5 years. No pre-operative tools are currently available to assess the recurrence risk tailored to every single patient. Recently liquid biopsy has shown interesting results in diagnosis, prognosis and treatment allocation strategies in other types of cancers, since its ability to identify circulating tumor cells (CTCs) derived from the primary tumor. Those cells were advocated to be responsible for the majority of cases of recurrence and cancer-related deaths for HCC. In fact, after being modified by the epithelial-mesenchymal transition, CTCs circulate as "seeds" in peripheral blood, then reach the target organ as dormant cells which could be subsequently "awakened" and activated, and then initiate metastasis. Their presence may justify the disagreement registered in terms of efficacy of anatomic vs non-anatomic resections, particularly in the case of microvascular invasion, which has been recently pointed as a histological sign of the spread of those cells. Thus, their presence, also in the early stages, may justify the recurrence event also in the contest of liver transplant. Understanding the mechanism behind the tumor progression may allow improving the treatment selection according to the biological patient-based characteristics. Moreover, it may drive the development of novel biological tailored tests which could address a specific patient to neoadjuvant or adjuvant strategies, and in perspective, it could also become a new method to allocate organs for transplantation, according to the risk of relapse after liver transplant. The present paper will describe the most recent evidence on the role of CTCs in determining the relapse of HCC, highlighting their potential clinical implication as novel tumor behavior biomarkers able to influence the surgical choice.
Collapse
Affiliation(s)
- Francesca Carissimi
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
| | | | - Livia Salmi
- Department of Translational Medicine, Università del Piemonte Orientale, Novara 28100, Italy
| | - Cristina Ciulli
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
| | - Linda Roccamatisi
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
| | - Giuseppe Cordaro
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
| | - Venkata Ramana Mallela
- Department of Translational Medicine, Università del Piemonte Orientale, Novara 28100, Italy
| | - Rosalba Minisini
- Department of Translational Medicine, Università del Piemonte Orientale, Novara 28100, Italy
| | - Biagio Eugenio Leone
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
- Unit of Pathology, San Gerardo Hospital, Monza 20900, Italy
| | - Matteo Donadon
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Clinical and Research Hospital-Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Italy
| | - Guido Torzilli
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Clinical and Research Hospital-Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Italy
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale, Novara 28100, Italy
| | - Fabrizio Romano
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
- Department of Medicine and Surgery, University of Milan-Bicocca, Monza 20900, Italy
| | - Simone Famularo
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Clinical and Research Hospital-Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Italy
| |
Collapse
|
|
32
|
Shi X, Tu S, Zhu L. Risk characteristics with seven epithelial-mesenchymal transition-related genes are used to predict the prognosis of patients with hepatocellular carcinoma. J Gastrointest Oncol 2021; 12:1884-1894. [PMID: 34532136 DOI: 10.21037/jgo-21-394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 08/16/2021] [Indexed: 11/06/2022] Open
Abstract
Background Epithelial-mesenchymal transition (EMT)-related genes (ERGs) have been shown to play an important role in cancer invasion, tumor resistance, and tumor metastasis of hepatocellular carcinoma. This study sought to examine the prognostic value of ERGs and other pre-hepatoma genes. Methods Relevant data from The Cancer Genome Atlas (TCGA) were analyzed and synthesized. Specifically, 1,014 ERGs were downloaded and subject to a gene set enrichment analysis; 318 different EAG expressions were found, and the possible molecular mechanism of EAG was predicted by GO analysis and KEGG analysis. To determine the prediction of ERGS, a Cox regression model was used to establish a risk hypothesis. Based on risk patterns, patients were divided into high- or low-risk groups. Kaplan-Meier and receiver operating characteristic (ROC) curves confirmed the predictive value of the model. Results Seven prognostically relevant ERGs (i.e., ECT2, EZH2, MYCN, ROR2, SPP1, SQSTM1, and STC2) were identified. Using Cox's regression analysis method, appropriate cases were selected to establish a new risk prediction model. Under the risk model, the overall survival rate of the low-risk group samples was higher than that of the high-risk group samples (P<0.00001). Conclusions In short, we developed a risk model for liver cancer based on ERGs terminology. This model improve the postpartum treatment of patients with liver cancer.
Collapse
Affiliation(s)
- Xianqing Shi
- Department of Oncology, Liyang People's Hospital, Liyang, China
| | - Shuhuan Tu
- Department of Oncology, Liyang People's Hospital, Liyang, China
| | - Liqun Zhu
- Department of Oncology, Liyang People's Hospital, Liyang, China
| |
Collapse
|
|
33
|
Ye Y, Yu F, Li Z, Xie Y, Yu X. RNA binding protein serine/arginine splicing factor 1 promotes the proliferation, migration and invasion of hepatocellular carcinoma by interacting with RecQ protein-like 4 mRNA. Bioengineered 2021; 12:6144-6154. [PMID: 34486474 PMCID: PMC8806490 DOI: 10.1080/21655979.2021.1972785] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Abnormally high expression of RecQ protein-like 4 (RECQL4) has been observed in many cancers, including hepatocellular carcinoma (HCC). We aimed to explore the effects of RECQL4 on HCC progression and the possible mechanisms. RECQL4 expression in HCC tissues and its correlation with the prognosis of HCC patients were analyzed using GEPIA2 and UALCAN databases. After detecting RECQL4 levels in several human HC cell lines, RECQL4 was silenced by siRNA transfection. Cell viability, migration and invasion were tested with CCK-8, wound healing and transwell assays. The levels of epithelial–mesenchymal transition (EMT) proteins were evaluated by western blotting. The ENCORI database was adopted for the analysis of the correlation between RECQL4 and serine/arginine splicing factor 1 (SRSF1) in HCC tissues. RNA immunoprecipitation and actinomycin D addition assay were employed to evaluate the combination of these two genes. SRSF1 was overexpressed to assess the biological function of HCC cells with RECQL4 silencing. Results suggested that RECQL4 was overexpressed in HCC tissues and cell lines, which was related to poor prognosis of HCC patients. RECQL4 loss-of-function repressed the proliferation, migration, invasion and EMT of HCC cells. RECQL4 was positively correlated with SRSF1 in HCC tissues. Moreover, SRSF1 was confirmed as an RNA binding protein of RECQL4. Further experiments found that SRSF1 knockdown reduced the stability of RECQL4 mRNA. Rescue assays indicated that SRSF1 overexpression crippled the braking effects of RECQL4 knockdown on the progression of HCC cells. Collectively, SRSF1 can bind to RECQL4 mRNA and enhance its stability, thereby promoting the progression of HCC.
Collapse
Affiliation(s)
- Ying Ye
- Wuchang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei, China
| | - Feng Yu
- Wuchang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei, China
| | - Zhao Li
- Wuchang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei, China
| | - Yaping Xie
- Wuchang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei, China
| | - Xiaohong Yu
- Wuchang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei, China
| |
Collapse
|
|
34
|
Huan L. Efficacy analysis of combined detection of 5 Serological Tumor markers including MIF and PIVKA-II for early diagnosis of Primary Hepatic Cancer. Pak J Med Sci 2021; 37:1456-1460. [PMID: 34475930 PMCID: PMC8377914 DOI: 10.12669/pjms.37.5.4264] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 04/23/2021] [Accepted: 05/02/2021] [Indexed: 12/22/2022] Open
Abstract
Objectives: To investigate the efficacy of combined detection of 5 serological tumor markers including macrophage migration inhibitory factor (MIF) and abnormal prothrombin (PIVKA-II) in the early diagnosis of primary liver cancer. Methods: A total of 90 patients with suspected primary liver cancer admitted to our hospital from January 2016 to May 2017 were selected as the research subjects. All patients were examined by imaging and histopathology. Enzyme-linked immunosorbent assay (ELISA) was used to detect serum MIF, GP73 and PIVKA-II. Automatic electrochemiluminescence immunoassay system was used to detect serum AFP and AFP-L3. The diagnostic value of single and combined detection of five serological tumor markers for primary liver cancer was compared and analyzed. Results: Of the 90 suspected patients with primary liver cancer, thirty-seven were excluded and 53 were confirmed. From serum MIF diagnosis, fifty-three patients had positive results for primary liver cancer, of which eight had false positive results, with a sensitivity of 84.91%, a specificity of 78.38%, and an accuracy of 82.22%, respectively. From serum GP73 diagnosis, fifty-six patients had positive results for primary liver cancer, of which 10 had false positive results, with a sensitivity of 86.79%, a specificity of 72.97%, and an accuracy of 81.11%, respectively. From serum PIVKA-II diagnosis, 48 patients had positive results for primary liver cancer, of which seven had false positive results, with the sensitivity of 77.36%, the specificity of 81.08%, and the accuracy of 78.89%, respectively. From serum AFP-L3 diagnosis, fifty-two patients had positive results for primary liver cancer, of which nine had false positive results, with a sensitivity of 81.13%, a specificity of 75.68%, and an accuracy of 78.89% respectively. From serum AFP diagnosis, 57 patients had positive results for primary liver cancer, of which seven had false positive results, with a sensitivity of 83.02%, the specificity of 81.08%, and an accuracy of 82.22%, respectively. From the combined diagnosis of 5 serological tumor markers, fifty-three patients had positive results for primary liver cancer, of which one had a false positive result, with a sensitivity of 98.11%, a specificity of 97.30%, and an accuracy of 97.78%, respectively. Combined diagnosis has significantly higher sensitivity, specificity and accuracy than a single diagnosis (P<0.05). Conclusion: Serum MIF, GP73, PIVKA-II, AFP-L3 and AFP all have certain diagnostic value for primary liver cancer; the combined detection of five serological tumor markers can significantly improve the sensitivity, specificity and accuracy of the diagnosis of primary liver cancer, with higher diagnostic value.
Collapse
Affiliation(s)
- Li Huan
- Li Huan Department of Clinical Laboratory, Tangshan People's Hospital, Tangshan, Hebei, 063000, China
| |
Collapse
|
|
35
|
Chen S, Zhao E. Development and validation of a robust epithelial-mesenchymal transition (EMT)-related prognostic signature for hepatocellular carcinoma. Clin Res Hepatol Gastroenterol 2021; 45:101587. [PMID: 33662631 DOI: 10.1016/j.clinre.2020.101587] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 11/14/2020] [Accepted: 11/24/2020] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Epithelial-to-mesenchymal transition (EMT) is an essential biological process of cancer progression associated with increased metastatic potential and initiation. Herein, we aimed to develop and validate a robust EMT-related prognostic signature that could predict the prognosis of patients with hepatocellular carcinoma (HCC). METHODS Messenger RNA expression matrix and clinicopathological data were retrieved from The Cancer Genome Atlas (TCGA) and identified differentially expressed genes (DEGs) between HCC tissues and adjacent non-tumor samples. Univariate Cox regression analysis, least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox regression analysis were performed to establish a prognosis signature. Kaplan-Meier survival curve, time-dependent receiver operating characteristic (ROC), multivariate Cox regression analysis, nomogram, C-index, and decision curve analysis (DCA) were performed to investigate the prognostic performance of the signature. The prognostic performance of the new signature was further validated in an independent external cohort. A support vector machine (SVM) approach was performed to evaluate the diagnostic value of the identified genes. RESULTS A seven-gene signature was formulated to classify patients into high-risk and low-risk groups with discrepant overall survival (OS) in two cohorts (all P < 0.0001), and the former illustrated shorter survival time than the latter even stratified by various groups. The new signature has presented an excellent performance for predicting survival prognosis. Multivariate analysis showed that the signature was an independent risk factor for HCC. The SVM classifier based on the seven genes presented an excellent diagnostic power in differentiating early HCC and normal tissues. Gene Set Enrichment Analyses (GSEA) demonstrated multiple biological processes and pathways to provide novel insights into the development of HCC. CONCLUSION We established and validated a prognostic signature based on EMT-related genes with good predictive value for HCC survival. The diagnostic performance of the signature had been demonstrated to accurately distinguish early HCC from control individuals.
Collapse
Affiliation(s)
- Shimin Chen
- Department of Gastroenterology, Traditional Chinese Medical Hospital of Taihe Country, Taihe, 236600, China.
| | - Enfa Zhao
- Department of Structural Heart Disease, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| |
Collapse
|
|
36
|
Santoni M, Iacovelli R, Colonna V, Klinz S, Mauri G, Nuti M. Antitumor effects of the multi-target tyrosine kinase inhibitor cabozantinib: a comprehensive review of the preclinical evidence. Expert Rev Anticancer Ther 2021; 21:1029-1054. [PMID: 34445927 DOI: 10.1080/14737140.2021.1919090] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Altered receptor tyrosine kinase (RTK) signaling contributes to tumorigenesis and suppression of immune-mediated destruction of cancer cells. Cabozantinib is an oral tyrosine kinase inhibitor that inhibits several RTKs involved in tumorigenesis, and is approved for the treatment of patients with progressive metastatic medullary thyroid cancer, advanced renal cell carcinoma, and hepatocellular carcinoma that has been previously treated with sorafenib. AREAS COVERED We present an up-to-date evaluation of preclinical evidence for RTK inhibition with cabozantinib, specifically VEGFR, MET, KIT, RET, AXL, FLT3, and associated antitumor effects. Preclinical investigations of cabozantinib in combination with other anticancer drugs are also reviewed. EXPERT OPINION Preclinical evidence shows that cabozantinib has antitumor activity against various cancer cells and exhibits synergy with other anticancer agents, including immune checkpoint inhibitors and hormone receptor or metabolic pathway inhibitors. Further optimization of cabozantinib treatment requires the identification of biomarkers of response and resistance, and exploration of complementary drug targets. Investigation of mechanisms of adaptive resistance, such as epithelial to mesenchymal transition (cancer intrinsic) and immunomodulation by the tumor microenvironment (cancer extrinsic), as well as identification of novel drug targets based on characterization of cancer stem cell metabolomic phenotypes, appear to be promising approaches.
Collapse
Affiliation(s)
- Matteo Santoni
- MD, U.O.C. Medical Oncology, Macerata Hospital, Macerata, Italy
| | - Roberto Iacovelli
- Medical Oncologist, Medical Oncology Unit, Fondazione Policlinico Agostino Gemelli IRCCS, Roma, Italy
| | - Valentina Colonna
- Global Medical Development Director, Global Oncology R&D, Ipsen S.p.A., Milano, Italy
| | - Stephan Klinz
- Senior Director, Translational Medicine & Biomarkers, Ipsen, United States, MA, USA
| | - Giorgio Mauri
- Medical Advisor Oncology, Ipsen S.p.A., Milano, Italy
| | - Marianna Nuti
- Professor, Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| |
Collapse
|
|
37
|
Li Y, Li T, Zhou D, Wei J, Li Z, Li X, Jia S, Ouyang Q, Qi S, Chen Z, Zhang B, Yu J, Jia J, Xu A, Huang J. Role of tight junction-associated MARVEL protein marvelD3 in migration and epithelial-mesenchymal transition of hepatocellular carcinoma. Cell Adh Migr 2021; 15:249-260. [PMID: 34338154 PMCID: PMC8331009 DOI: 10.1080/19336918.2021.1958441] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/29/2022] Open
Abstract
MarvelD3, a recently identified tight junction membrane protein, could be associated with hepatocellular carcinoma (HCC). We aimed to investigate the role of marvelD3 in Epithelial-Mesenchymal Transition (EMT) and migration of HCC and explore the underlying molecular mechanisms. First, we assessed marvlD3 expression in HCC and normal liver tissues and found loss of marvelD3 expression was significantly correlated with the occurrence and TNM stage of HCC. Second, we detected that marvelD3 was downregulated in HCC cells with transforming growth factor β1 and snail/slug-induced EMT. Finally, we analyzed expression of marvelD3 protein was significantly associated with EMT and the NF-κB signaling pathway. Our study demonstrated that MarvelD3 inhibited EMT and migration of HCC cells along with inhibiting NF-κB signaling pathway.Abbreviations: HCC, Hepatocellular carcinoma; TJ, Tight junction; MARVEL, MAL and related proteins for vesicle trafficking and membrane link; EMT, Epithelial-mesenchymal transition; NF-κB, Nuclear factor kappa B; TAMPs, Tight junction-associated marvel proteins; TGF-β1, Transforming growth factor-β1; MMP9, matrix metallopeptidase 9; RT-PCR, Real-time PCR; IHC, Immunohistochemistry; IF, Immunofluorescence.
Collapse
Affiliation(s)
- Yanmeng Li
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Teng Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Donghu Zhou
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jia Wei
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhenkun Li
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiaojin Li
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Siyu Jia
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Qin Ouyang
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Saiping Qi
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhibin Chen
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Bei Zhang
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jing Yu
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Anjian Xu
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jian Huang
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| |
Collapse
|
|
38
|
Lv D, Chen L, Du L, Zhou L, Tang H. Emerging Regulatory Mechanisms Involved in Liver Cancer Stem Cell Properties in Hepatocellular Carcinoma. Front Cell Dev Biol 2021; 9:691410. [PMID: 34368140 PMCID: PMC8339910 DOI: 10.3389/fcell.2021.691410] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 07/01/2021] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer and one of the leading causes of cancer-related deaths worldwide. A growing body of evidence supports the hypothesis that HCC is driven by a population of cells called liver cancer stem cells (LCSCs). LCSCs have been proposed to contribute to malignant HCC progression, including promoting tumor occurrence and growth, mediating tumor metastasis, and treatment resistance, but the regulatory mechanism of LCSCs in HCC remains unclear. Understanding the signaling pathways responsible for LCSC maintenance and survival may provide opportunities to improve patient outcomes. Here, we review the current literature about the origin of LCSCs and the niche composition, describe the current evidence of signaling pathways that mediate LCSC stemness, then highlight several mechanisms that modulate LCSC properties in HCC progression, and finally, summarize the new developments in therapeutic strategies targeting LCSCs markers and regulatory pathways.
Collapse
Affiliation(s)
- Duoduo Lv
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Liyu Chen
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Lingyao Du
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Lingyun Zhou
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China.,State Key Laboratory of Biotherapy and Center of Infectious Diseases, Division of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| |
Collapse
|
|
39
|
Öz E, Tüylü Küçükkılınç T. Combined effect of fulvestrant and low dose BPA: comparative implications on EMT, apoptosis, and TGF-β1 signaling in HepG2 cells. Drug Chem Toxicol 2021; 45:2285-2291. [PMID: 34100320 DOI: 10.1080/01480545.2021.1935368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Bisphenol A (BPA) is an endocrine-disrupting chemical utilized in the manufacture of food packaging, dental materials, medical devices, children's toys, and baby products. Numerous studies have indicated the role of BPA in the etiology of many diseases such as diabetes, cardiovascular diseases, obesity, cancer, and chemotherapeutic resistance. However, the effects of BPA- chemotherapeutic combination remain to be investigated in different cell lines. Here, we demonstrate that low dose BPA and fulvestrant (estrogen receptor antagonist) combination synergistically decrease proliferation, promote cell migration and mesenchymal transition, switching from E-cadherin to N-cadherin expression Hepg2 cells. Moreover, we determined that low dose BPA may evoke susceptibility to apoptosis in HepG2 cells. The mechanism underlying these effects has been identified as increased TGF-β1 signaling. Our results provide an experimental basis for evaluating the potential health risks of low-dose BPA for fulvestrant therapy in hepatocytes.
Collapse
Affiliation(s)
- Esin Öz
- Department of Biochemistry, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | | |
Collapse
|
|
40
|
Dian MJ, Li J, Zhang XL, Li ZJ, Zhou Y, Zhou W, Zhong QL, Pang WQ, Lin XL, Liu T, Liu YA, Li YL, Han LX, Zhao WT, Jia JS, Xiao SJ, Xiao D, Xia JW, Hao WC. MST4 negatively regulates the EMT, invasion and metastasis of HCC cells by inactivating PI3K/AKT/Snail1 axis. J Cancer 2021; 12:4463-4477. [PMID: 34149910 PMCID: PMC8210547 DOI: 10.7150/jca.60008] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 05/08/2021] [Indexed: 12/23/2022] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has a poor prognosis due to the high incidence of invasion and metastasis-related progression. However, the underlying mechanism remains elusive, and valuable biomarkers for predicting invasion, metastasis, and poor prognosis of HCC patients are still lacking. Methods: Immunohistochemistry (IHC) was performed on HCC tissues (n = 325), and the correlations between MST4 expression of the clinical HCC tissues, the clinicopathologic features, and survival were further evaluated. The effects of MST4 on HCC cell migratory and invasive properties in vitro were evaluated by Transwell and Boyden assays. The intrahepatic metastasis mouse model was established to evaluate the HCC metastasis in vivo. The PI3K inhibitor, LY294002, and a specific siRNA against Snail1 were used to investigate the roles of PI3K/AKT pathway and Snail1 in MST4-regulated EMT, migration, and invasion of HCC cells, respectively. Results: In this study, by comprehensively analyzing our clinical data, we discovered that low MST4 expression is highly associated with the advanced progression of HCC and serves as a prognostic biomarker for HCC patients of clinical-stage III-IV. Functional studies indicate that MST4 inactivation induces epithelial-to-mesenchymal transition (EMT) of HCC cells, promotes their migratory and invasive potential in vitro, and facilitates their intrahepatic metastasis in vivo, whereas MST4 overexpression exhibits the opposite phenotypes. Mechanistically, MST4 inactivation elevates the expression and nuclear translocation of Snail1, a key EMT transcription factor (EMT-TF), through the PI3K/AKT signaling pathway, thus inducing the EMT phenotype of HCC cells, and enhancing their invasive and metastatic potential. Moreover, a negative correlation between MST4 and p-AKT, Snail1, and Ki67 and a positive correlation between MST4 and E-cadherin were determined in clinical HCC samples. Conclusions: Our findings indicate that MST4 suppresses EMT, invasion, and metastasis of HCC cells by modulating the PI3K/AKT/Snail1 axis, suggesting that MST4 may be a potential prognostic biomarker for aggressive and metastatic HCC.
Collapse
Affiliation(s)
- Mei-Juan Dian
- Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.,Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China
| | - Jing Li
- Radiotherapy Center, the First People's Hospital of Chenzhou, Xiangnan University, Chenzhou 423000, China
| | - Xiao-Ling Zhang
- Department of Physiology, Faculty of Basic Medical Sciences, Guilin Medical University, Guilin 541004, China
| | - Zi-Jian Li
- Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Ying Zhou
- Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Wei Zhou
- Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Qiu-Ling Zhong
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Wen-Qian Pang
- Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Xiao-Lin Lin
- Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Tao Liu
- Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yi-An Liu
- Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yong-Long Li
- Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China
| | - Liu-Xin Han
- The third people's hospital of Kunming (The Sixth Affiliated Hospital of Dali University), Kunming 650041, China
| | - Wen-Tao Zhao
- Department of Gastrointestinal Oncology, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center), Kunming 650118, China
| | - Jun-Shuang Jia
- Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Sheng-Jun Xiao
- Department of Pathology, the Second Affiliated Hospital, Guilin Medical University, Guilin 541199, China
| | - Dong Xiao
- Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.,Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China
| | - Jia-Wei Xia
- The third people's hospital of Kunming (The Sixth Affiliated Hospital of Dali University), Kunming 650041, China
| | - Wei-Chao Hao
- Department of Oncology, The First Affiliation Hospital of Guangdong Pharmaceutical University, Guangzhou 510062, China
| |
Collapse
|
|
41
|
Munakarmi S, Shrestha J, Shin HB, Lee GH, Jeong YJ. 3,3'-Diindolylmethane Suppresses the Growth of Hepatocellular Carcinoma by Regulating Its Invasion, Migration, and ER Stress-Mediated Mitochondrial Apoptosis. Cells 2021; 10:cells10051178. [PMID: 34066056 PMCID: PMC8151225 DOI: 10.3390/cells10051178] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/30/2021] [Accepted: 05/05/2021] [Indexed: 12/30/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death worldwide with limited treatment options. Biomarker-based active phenolic flavonoids isolated from medicinal plants might shed some light on potential therapeutics for treating HCC. 3,3′-diindolylmethane (DIM) is a unique biologically active dimer of indole-3-carbinol (I3C), a phytochemical compound derived from Brassica species of cruciferous vegetables—such as broccoli, kale, cabbage, and cauliflower. It has anti-cancer effects on various cancers such as breast cancer, prostate cancer, endometrial cancer, and colon cancer. However, the molecular mechanism of DIM involved in reducing cancer risk and/or enhancing therapy remains unknown. The aim of the present study was to evaluate anti-cancer and therapeutic effects of DIM in human hepatoma cell lines Hep3B and HuhCell proliferation was measured with MTT and trypan blue colony formation assays. Migration, invasion, and apoptosis were measured with Transwell assays and flow cytometry analyses. Reactive oxygen species (ROS) intensity and the loss in mitochondrial membrane potential of Hep3B and Huh7 cells were determined using dihydroethidium (DHE) staining and tetramethylrhodamine ethyl ester dye. Results showed that DIM significantly suppressed HCC cell growth, proliferation, migration, and invasion in a concentration-dependent manner. Furthermore, DIM treatment activated caspase-dependent apoptotic pathway and suppressed epithelial–mesenchymal transition (EMT) via ER stress and unfolded protein response (UPR). Taken together, our results suggest that DIM is a potential anticancer drug for HCC therapy by targeting ER-stress/UPR.
Collapse
Affiliation(s)
- Suvesh Munakarmi
- Laboratory of Liver Regeneration, Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju 54907, Korea;
| | - Juna Shrestha
- Alka Hospital Private Limited, Jwalakhel, Kathmandu 446010, Nepal;
| | - Hyun-Beak Shin
- Department of Surgery, Jeonbuk National University Hospital, Jeonju 54907, Korea;
| | - Geum-Hwa Lee
- Department of Pharmacology and New Drug Development Research Institute, Jeonbuk National University Hospital, Jeonju 54907, Korea;
| | - Yeon-Jun Jeong
- Laboratory of Liver Regeneration, Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju 54907, Korea;
- Department of Surgery, Jeonbuk National University Hospital, Jeonju 54907, Korea;
- Correspondence:
| |
Collapse
|
|
42
|
Hu S, Liu J, Feng S, Wang Y, Liu H. LncRNA SUMO1P3 acts as a prognostic biomarker and promotes hepatocellular carcinoma growth and metastasis. Aging (Albany NY) 2021; 13:12479-12492. [PMID: 33902004 PMCID: PMC8148505 DOI: 10.18632/aging.202921] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 01/04/2021] [Indexed: 04/10/2023]
Abstract
Long noncoding RNAs (lncRNAs) are involved in the progression of various cancers, including hepatocellular carcinoma (HCC). However, the biological functions of lncRNA small ubiquitin-like modifier 1 pseudogene 3 (SUMO1P3) and the underlying mechanisms remain unclear. In this study, we revealed that SUMO1P3 expression was enhanced in HCC tissues and cell lines, positively associating with tumor size and number, poor differentiation, lymphatic and distant metastasis, TNM stage, and poor prognosis in HCC patients. In vitro assays showed that SUMO1P3 depletion reduced HCC cell viability and proliferation by hindering cyclin D1 expression and Akt phosphorylation. SUMO1P3 knockdown induced HCC cell apoptosis, as indicated by increased Bax and cleaved caspase-3 expression and the decreased Bcl-2 level. SUMO1P3 silencing suppressed HCC cell migration and invasion by increasing epithelial marker E-cadherin expression and decreasing mesenchymal marker vimentin expression, as well as reducing matrix metalloproteinase (MMP)-2 and MMP-9 levels. Consistently, SUMO1P3 depletion in HCC cells retarded tumor growth and lung metastasis in vivo. Overall, these results supported the applicability of SUMO1P3 as a useful predictor of HCC prognosis and a potential therapeutic target for HCC patients.
Collapse
Affiliation(s)
- Shu Hu
- Medical College, Henan University of Science and Technology, Luoyang 471003, Henan, China
| | - Jiancheng Liu
- Medical College, Henan University of Science and Technology, Luoyang 471003, Henan, China
| | - Shuying Feng
- Medical College, Henan University of Science and Technology, Luoyang 471003, Henan, China
| | - Yue Wang
- Medical College, Henan University of Science and Technology, Luoyang 471003, Henan, China
| | - Hongchao Liu
- Medical College, Henan University of Science and Technology, Luoyang 471003, Henan, China
| |
Collapse
|
|
43
|
Interplay of autophagy and cancer stem cells in hepatocellular carcinoma. Mol Biol Rep 2021; 48:3695-3717. [PMID: 33893928 DOI: 10.1007/s11033-021-06334-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Accepted: 04/02/2021] [Indexed: 12/22/2022]
Abstract
Liver cancer is the sixth most common cancer and the fourth leading cause of cancer deaths in the world. The most common type of liver cancers is hepatocellular carcinoma (HCC). Autophagy is the cellular digestion of harmful components by sequestering the waste products into autophagosomes followed by lysosomal degradation for the maintenance of cellular homeostasis. The impairment of autophagy is highly associated with the development and progression of HCC although autophagy may be involved in tumour-suppressing cellular events. In regards to its protecting role, autophagy also shelters the cells from anoikis- a programmed cell death in anchorage-dependent cells detached from the surrounding extracellular matrix which facilitates metastasis in HCC. Liver cancer stem cells (LCSCs) have the ability for self-renewal and differentiation and are associated with the development and progression of HCC by regulating stemness, resistance and angiogenesis. Interestingly, autophagy is also known to regulate normal stem cells by promoting cellular survival and differentiation and maintaining cellular homeostasis. In this review, we discuss the basal autophagic mechanisms and double-faceted roles of autophagy as both tumour suppressor and tumour promoter in HCC, as well as its association with and contribution to self-renewal and differentiation of LCSCs.
Collapse
|
|
44
|
Shizu R, Ishimura M, Nobusawa S, Hosaka T, Sasaki T, Kakizaki S, Yoshinari K. The influence of the long-term chemical activation of the nuclear receptor pregnane X receptor (PXR) on liver carcinogenesis in mice. Arch Toxicol 2021; 95:1089-1102. [PMID: 33398415 DOI: 10.1007/s00204-020-02955-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 11/12/2020] [Indexed: 12/13/2022]
Abstract
Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are nuclear receptors that are highly expressed in the liver and activated by numerous chemicals. While CAR activation by its activators, such as phenobarbital (PB), induces hepatocyte proliferation and liver carcinogenesis in rodents, it remains unclear whether PXR activation drives liver cancer. To investigate the influence of PXR activation on liver carcinogenesis, we treated mice with the PXR activator pregnenolone 16α-carbonitrile (PCN) with or without PB following tumor initiation with diethylnitrosamine (DEN). After 20 weeks of treatment, preneoplastic lesions detected by immunostaining with an anti-KRT8/18 antibody were observed in PB-treated but not PCN-treated mice, and PCN cotreatment augmented the formation of preneoplastic lesions by PB. After 35 weeks of treatment, macroscopic observations indicated that PB-treated and PB/PCN-cotreated mice had increased numbers of liver tumors compared to control and PCN-treated mice. In the pathological analyses of liver sections, all the mice in the PB and PB/PCN groups developed carcinoma and/or eosinophilic adenoma, but in the PB/PCN group, the multiplicity of carcinoma and eosinophilic adenoma was significantly reduced and the size of carcinoma showed a tendency to decrease. No mouse in the control or PCN-treated group developed such tumors. Differentially expressed gene (DEG) and gene set enrichment analyses in combination with RNA sequencing suggested the increased expression of genes related to epithelial-mesenchymal transition (EMT) in mice cotreated with PCN and PB compared to those treated with PB alone. Changes in the hepatic mRNA levels of epithelial marker genes supported the results of the transcriptome analyses. In conclusion, the present results suggest that PXR activation does not promote hepatocarcinogenesis in contrast to CAR and rather attenuates CAR-mediated liver cancer development by suppressing the EMT of liver cancer cells in rodents.
Collapse
Affiliation(s)
- Ryota Shizu
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan
| | - Mai Ishimura
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan
| | - Sumihito Nobusawa
- Department of Human Pathology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan
| | - Takuomi Hosaka
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan
| | - Takamitsu Sasaki
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan
| | - Satoru Kakizaki
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan
| | - Kouichi Yoshinari
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.
| |
Collapse
|
|
45
|
Fawzy MS, Toraih EA. MicroRNA signatures as predictive biomarkers in transarterial chemoembolization‐treated hepatocellular carcinoma. PRECISION MEDICAL SCIENCES 2021. [DOI: 10.1002/prm2.12031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Affiliation(s)
- Manal S. Fawzy
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine Suez Canal University Ismailia Egypt
- Biochemistry Department, Faculty of Medicine Northern Border University Arar KSA
| | - Eman A. Toraih
- Department of Surgery Tulane University, School of Medicine New Orleans Louisiana USA
- Genetics Unit, Department of Histology and Cell Biology, Faculty of Medicine Suez Canal University Ismailia Egypt
| |
Collapse
|
|
46
|
Liu Z, Sun J, Wang X, Cao Z. MicroRNA-129-5p promotes proliferation and metastasis of hepatocellular carcinoma by regulating the BMP2 gene. Exp Ther Med 2021; 21:257. [PMID: 33603864 DOI: 10.3892/etm.2021.9688] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 11/26/2020] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignant tumor that poses a serious threat to human health. Due to its occult onset and rapid development, HCC is a challenge to diagnose early and effectively treat, and thus patients with HCC often have an unfavorable prognosis. MicroRNA (miR)-129 and its target gene play an important role in the regulation of various diseases. Therefore, the aim of the present study was to investigate the role and mechanism of action for miR-129-5p in the development of HCC. Quantitative results of clinical samples analyzed using reverse transcription-quantitative PCR suggested that miR-129-5p had a significantly lower expression level in tumoral tissues compared with corresponding peritumoral tissues. Overexpression of miR-129-5p in HCC cells was performed using a transfection technique, followed by MTT, Transwell, invasion and wound healing assays to detect the effect of miR-129-5p on the cell cytotoxicity and metastasis of liver cancer in vitro. The downstream target gene of miR-129-5p, bone morphogenetic protein 2 (BMP2), was determined using a luciferase reporter assay. Overexpression of miR-129-5p played a vital role in decreasing cytotoxicity and promoting metastasis of HCC, which may be attributed to its inhibitory effect on the expression of its target gene, BMP2. In clinical samples, miR-129-5p expression levels were found to be negatively correlated with BMP2 and closely associated with HCC metastasis and infiltration. Collectively, the results suggested that miR-129-5p may contribute to proliferation and metastasis of HCC through its target gene, BMP2, and thus may be a potential novel therapeutic target for the treatment of HCC.
Collapse
Affiliation(s)
- Zengyao Liu
- Department of Intervention, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Jiefei Sun
- Interventional Catheter Therapy Section Office, Zhaodong Renmin Hospital, Zhaodong, Heilongjiang 151100, P.R. China
| | - Xiaochun Wang
- Department of Nursing, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Zhenyuan Cao
- Department of Intervention, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| |
Collapse
|
|
47
|
Shrestha R, Bridle KR, Crawford DHG, Jayachandran A. Immune checkpoint molecules are regulated by transforming growth factor (TGF)- β1-induced epithelial-to-mesenchymal transition in hepatocellular carcinoma. Int J Med Sci 2021; 18:2466-2479. [PMID: 34104078 PMCID: PMC8176170 DOI: 10.7150/ijms.54239] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 03/30/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with a high mortality rate. Epithelial-to-mesenchymal transition (EMT) confers cancer cells with immune evasive ability by modulating the expression of immune checkpoints in many cancers. Thus, the aim of our study is to examine the interplay between EMT and immune checkpoint molecules in HCC. A reversible EMT model was utilised with transforming growth factor (TGF)-β1 as an EMT inducer for HCC cell lines Hep3B and PLC/PRF/5. HCC cells were treated with TGF-β1 for 72 h and the EMT status and immune checkpoint expression were examined. In addition, the migratory ability of HCC cells were examined using wound healing and transwell migration assays in the reversible EMT model. siRNA-mediated knockdown of immune checkpoint molecule, B7-H3, was further utilised to validate the association between TGF-β1-mediated EMT and immune checkpoint expression in HCC. In addition, a web-based platform, SurvExpress, was utilised to evaluate the association between expression of TGF-β1 in combination with immune checkpoint molecules and overall survival in HCC patients. We observed induction of EMT upon treatment of HCC cells with TGF-β1 revealed by reduced expression of epithelial markers along with increased expression of mesenchymal markers. Withdrawal of TGF-β1 reversed the process of EMT with elevated expression of epithelial markers and reduced expression of mesenchymal markers. TGF-β1 treatment elevated the migratory potential of HCC cells which was reversed following reversal assay. Notably, during TGF-β1-induced EMT, there was upregulation of immune checkpoint molecules PD-L1 and B7-H3. However, the reversal of EMT decreased the expression of PD-L1 and B7-H3. In addition, TGF-β1 driven EMT was reversed following knockdown of B7-H3 in both HCC cells further validating the interplay between TGF-β1-mediated EMT and immune checkpoint expression in HCC. Furthermore, the coordinate expression of TGF-β1 with PD-L1 (p=0.01487) and B7-H3 (p=0.009687) was correlated with poor overall survival in 422 HCC patients. Our study has demonstrated a close association between TGF-β1-mediated EMT and regulation of immune checkpoints in HCC.
Collapse
Affiliation(s)
- Ritu Shrestha
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, Queensland, Australia
| | - Kim R Bridle
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, Queensland, Australia
| | - Darrell H G Crawford
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, Queensland, Australia
| | - Aparna Jayachandran
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, Queensland, Australia.,Fiona Elsey Cancer Research Institute, Ballarat, Victoria, Australia
| |
Collapse
|
|
48
|
Min WP, Wei XF. Silencing SIX1 inhibits epithelial mesenchymal transition through regulating TGF-β/Smad2/3 signaling pathway in papillary thyroid carcinoma. Auris Nasus Larynx 2020; 48:487-495. [PMID: 33077306 DOI: 10.1016/j.anl.2020.10.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 09/29/2020] [Accepted: 10/01/2020] [Indexed: 12/30/2022]
Abstract
OBJECTIVE To investigate the sineoculis homeobox homolog 1 (SIX1) affect the epithelial mesenchymal transition (EMT) in papillary thyroid carcinoma (PTC) through regulating TGF-β/Smad2/3 signaling pathway. METHODS The SIX1 expression in cytological specimens, tissues or PTC cell lines was detected by qRT-PCR, western blotting or immunohistochemistry. A series of vitro experiments including flow cytometry, CCK-8, wound-healing and Transwell were used to evaluate the biological characteristics in a PTC cell line (NPA cells), which were divided into Blank, Negative control (NC), SIX1, SIX1-siRNA, LY-364947 (TGF-β/Smad2/3 pathway inhibitor) and SIX1 + LY-364947 groups. TGF-β/Smad2/3 pathway and EMT related protein expression were measured by qRT-PCR and western blotting. RESULTS SIX1 mRNA expression was increased in cytological specimens from PTC patients as compared with the non-toxic nodular goitre (NTG) patients. Moreover, compared with adjacent normal tissues, expressions of SIX1, N-cadherin and Vimentin were higher while E-cadherin was lower in PTC tissues; and SIX1 was positively correlated with N-cadherin and Vimentin but was negatively correlated with E-cadherin. Furthermore, the SIX1 expression was associated with histopathology, extrathyroidal extension (ETE), lymph node metastasis (LNM), pT stage, TNM stage, and distant metastasis. In addition, the expressions of TGFβ1, p-SMAD2/3, N-cadherin and Vimentin were downregulated in NPA cells after LY-364947 treatment with upregulated E-cadherin, decreased cell proliferation and metastasis, and enhanced cell apoptosis, which was reversed by SIX1 overexpression. CONCLUSION Silencing SIX1 can inhibit TGF-β/Smad2/3 pathway, thereby suppressing EMT in PTC, which may be a novel avenue for the treatment of PTC.
Collapse
Affiliation(s)
- Wen-Pu Min
- Department of Nuclear Medicine, The First People's Hospital of Jingzhou City, The First Affiliated Hospital of Yangtze University, Jingzhou 434000, Hubei Province, China
| | - Xiao-Feng Wei
- Department of Nuclear Medicine, The First People's Hospital of Jingzhou City, The First Affiliated Hospital of Yangtze University, Jingzhou 434000, Hubei Province, China.
| |
Collapse
|
|
49
|
Hu Y, Nie Q, Dai M, Chen F, Wu H. Histone Deacetylases Inhibit the Snail2-Mediated EMT During Metastasis of Hepatocellular Carcinoma Cells. Front Cell Dev Biol 2020; 8:752. [PMID: 32850856 PMCID: PMC7419474 DOI: 10.3389/fcell.2020.00752] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 07/17/2020] [Indexed: 12/31/2022] Open
Abstract
Snail2 has an important role in the epithelial-mesenchymal transition (EMT) and tumor metastasis. Here, we report that Snail2 is highly expressed during TGF-β induced EMT in HL-7702 cells. Additionally, overexpression of Snail2 successfully promotes the migration and invasion of these cells, both in vitro and in a mouse model. Furthermore, our results show that HDAC1 and HDAC3 could suppress the Snail2 gene promoter. Moreover, we find that the acetylation of H3K4 and H3K56 are significantly reduced during the EMT process of liver HL-7702 cells. Thus, our results indicate that HDAC1 and HDAC3 epigenetically suppress the expression of Snail2 during the EMT of liver cells, revealing an opposing function of HDACs during the migration of malignant tumors.
Collapse
Affiliation(s)
- Yue Hu
- Department of Gastrointestinal and Colorectal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Qing Nie
- Department of Gastrointestinal and Colorectal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Mingrui Dai
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, China
| | - Fangfang Chen
- Department of Gastrointestinal and Colorectal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Hui Wu
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, China.,Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun, China
| |
Collapse
|
|
50
|
Feng XM, Ma M, Li H. Therapeutic effect of entecavir combined with compound Biejia Ruangan tablets on liver fibrosis. Shijie Huaren Xiaohua Zazhi 2020; 28:558-562. [DOI: 10.11569/wcjd.v28.i13.558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Chronic hepatitis B (CHB) patients often suffer from chronic inflammatory stimulation for a long time and are prone to liver fibrosis. Antiviral therapy combined with traditional Chinese medicine is the main treatment for liver fibrosis. Acoustic radiation force imaging (ARFI) can be used to quantitatively evaluate the hardness of the liver, thus providing an imaging means for clinical noninvasive evaluation of anti-fibrosis effect.
AIM To evaluate the therapeutic effect of entecavir combined with compound Biejia Ruangan tablets on CHB liver fibrosis by ARFI.
METHODS Ninety-two patients with CHB liver fibrosis were selected as study subjects. All patients were treated with entecavir combined with compound Biejia Ruangan tablets. ARFI was performed before and after treatment. Meanwhile, the indexes of serum liver fibrosis and liver function were measured before and after treatment. The results were compared with those of liver biopsy.
RESULTS After treatment, serum alanine aminotransferase and aspartate aminotransferase, hyaluronic acid, type IV collagen, and laminin, and ARFI value decreased significantly (P < 0.05). ARFI values were positively correlated with the stages of liver fibrosis before and after treatment (r = 0.82, 0.84, P < 0.05).
CONCLUSION ARFI can accurately reflect the change of CHB liver fibrosis degree before and after treatment of entecavir and compound Biejia Ruangan tablets, and provides a new imaging method for curative effect evaluation.
Collapse
Affiliation(s)
- Xiang-Min Feng
- Department of Traditional Chinese Medicine, Jiaxing Xiuzhou Wangdian People's Hospital, Jiaxing 314011, Zhejiang Province, China
| | - Ming Ma
- Department of Ultrasonography, the Second Hospital of Jiaxing, Jiaxing 314000, Zhejiang Province, China
| | - Hao Li
- Department of Ultrasonography, Traditional Chinese Medicine Hospital of Hangzhou, Hangzhou 310013, Zhejiang Province, China
| |
Collapse
|