Cancer stem cells (CSCs) are now recognized as one of the major root causes of therapy failure and tumor recurrence in hepatocellular carcinoma (HCC). Early studies in the field focused primarily on ...the intrinsic regulators of CSC maintenance, but in recent years, mounting evidence has demonstrated the presence and role of extrinsic regulators in the tumor microenvironment (TME) in the control of liver CSCs. In addition to direct interaction with cellular components, noncellular components, including the extracellular matrix, hypoxia, nutrient deprivation, and secreted molecules within the tumor stroma and hepatitis viruses, also play a critical role in shaping the CSC niche. In this review, we highlight how various noncellular components in the TME play a role in regulating CSCs and how CSCs secrete components to interact with the TME to generate their own niche, working hand in hand to drive tumor physiology in HCC. In addition, we describe the potential clinical applications of these findings and propose perspectives on future research of noncellular components in the liver CSC niche.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, OILJ, SBCE, SBMB, UPUK
Abstract
Tumor lineage plasticity, considered a hallmark of cancer, denotes the phenomenon in which tumor cells co-opt developmental pathways to attain cellular plasticity, enabling them to evade ...targeted therapeutic interventions. However, the underlying molecular events remain largely elusive. Our recent study identified CD133/Prom1 in hepatocellular carcinoma (HCC) tumors to mark proliferative tumor-propagating cells with cancer stem cell-like properties, that follow a dedifferentiation trajectory towards a more embryonic state. Here we show SPINK1 to strongly associate with CD133 + HCC, and tumor dedifferentiation. Enhanced transcriptional activity of SPINK1 is mediated by promoter binding of ELF3, which like CD133, is found to increase following 5-FU and cisplatin treatment; while targeted depletion of CD133 will reduce both ELF3 and SPINK1. Functionally, SPINK1 overexpression promotes tumor initiation, self-renewal, and chemoresistance by driving a deregulated EGFR-ERK-CDK4/6-E2F2 signaling axis to induce dedifferentiation of HCC cells into their ancestral lineages. Depleting SPINK1 function by neutralizing antibody treatment or in vivo lentivirus-mediated
Spink1
knockdown dampens HCC cancer growth and their ability to resist chemotherapy. Targeting oncofetal SPINK1 may represent a promising therapeutic option for HCC treatment.
Nasopharyngeal carcinoma (NPC) is an Epstein‐Barr virus (EBV)‐associated epithelial malignancy. The high expression of BART‐miRNAs (miR‐BARTs) during latent EBV infection in NPC strongly supports ...their pathological importance in cancer progression. Recently, we found that several BART‐miRNAs work co‐operatively to modulate the DNA damage response (DDR) by reducing Ataxia‐telangiectasia‐mutated (ATM) activity. In this study, we further investigated the role of miR‐BARTs on DDR. The immunohistochemical study showed that the DNA repair gene, BRCA1, is consistently down‐regulated in primary NPCs. Using computer prediction programs and a series of reporter assays, we subsequently identified the negative regulatory role of BART2‐3p, BART12, BART17‐5p and BART19‐3p in BRCA1 expression. The ectopic expression of these four miR‐BARTs suppressed endogenous BRCA1 expression in EBV‐negative epithelial cell lines, whereas BRCA1 expression was enhanced by repressing endogenous miR‐BARTs activities in C666‐1 cells. More importantly, suppressing BRCA1 expression in nasopharyngeal epithelial cell lines using miR‐BART17‐5p and miR‐BART19‐3p mimics reduced the DNA repair capability and increased the cell sensitivity to the DNA‐damaging chemotherapeutic drugs, cisplatin and doxorubicin. Our findings suggest that miR‐BARTs play a novel role in DDR and may facilitate the development of effective NPC therapies.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
HCC is an aggressive disease with poor clinical outcome. Understanding the mechanisms that drive cancer stemness, which we now know is the root cause of therapy failure and tumor recurrence, is ...fundamental for designing improved therapeutic strategies. This study aims to identify molecular players specific to CD133 + HCC to better design drugs that can precisely interfere with cancer stem cells but not normal stem cell function.
Transcriptome profiling comparison of epithelial-specific "normal" CD133 + cells isolated from fetal and regenerating liver against "HCC" CD133 + cells isolated from proto-oncogene-driven and inflammation-associated HCC revealed preferential overexpression of SERPINA12 in HCC but not fetal and regenerating liver CD133 + cells. SERPINA12 upregulation in HCC is tightly associated with aggressive clinical and stemness features, including survival, tumor stage, cirrhosis, and stemness signatures. Enrichment of SERPINA12 in HCC is mediated by promoter binding of the well-recognized β-catenin effector TCF7L2 to drive SERPINA12 transcriptional activity. Functional characterization identified a unique and novel role of endogenous SERPINA12 in promoting self-renewal, therapy resistance, and metastatic abilities. Mechanistically, SERPINA12 functioned through binding to GRP78, resulting in a hyperactivated AKT/GSK3β/β-catenin signaling cascade, forming a positive feed-forward loop. Intravenous administration of rAAV8-shSERPINA12 sensitized HCC cells to sorafenib and impeded the cancer stem cell subset in an immunocompetent HCC mouse model.
Collectively, our findings revealed that SERPINA12 is preferentially overexpressed in epithelial HCC CD133 + cells and is a key contributor to HCC initiation and progression by driving an AKT/β-catenin feed-forward loop.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, OILJ, SBCE, SBMB, UPUK
Introduction: Compared with multivariate risk assessment, traditional category-based risk assessment (CRA) approaches for neonatal early-onset sepsis (EOS) screening are usually straightforward to ...use, do not require electronic devices, but are associated with higher rates of antibiotic use. This study aims to evaluate the performance of a novel enhanced CRA (eCRA) framework on EOS admissions and antibiotic use and to investigate whether a modified version with adjustments in risk factor weighting can allow its performance to match the EOS calculator while remaining easy to implement. Method: This is a prospective, single-center, two-phase observational study. Infants of all gestations delivered in a tertiary hospital in Hong Kong with risk factors or clinical features of EOS were recruited. Phase I: A novel eCRA framework (period 2) was compared with the CDC 2010-based protocol (period 1). Phase II: A modified eCRA framework was compared theoretically with the EOS calculator. EOS-specific admissions and antibiotic use were measured. Results: Phase I: 1,025 at-risk infants were recruited during period 2 and compared with 757 infants of period 1. Admissions and antibiotic use decreased from 45.8% to 29.4% and 41.1% to 28.2%, respectively. Antibiotics among those at-risk but well-appearing infants decreased from 25.3% to 16.3% (p < 0.001 for all). Phase II: antibiotic use was similar (7.3 vs. 6.4%, p = 0.42) between the modified eCRA framework and the EOS calculator. Conclusions: An eCRA framework can effectively and safely provide individualized guidance for EOS screening without the need for tools such as the EOS calculator.
Abstract
Nasopharyngeal carcinoma (NPC) is a highly invasive epithelial malignancy that is prevalence in southern China and Southeast Asia. It is well-known to be associated with latent Epstein-Barr ...virus (EBV) infection. By using small RNA sequencing, we previously established a comprehensive miRNA profile in a panel of NPC samples and revealed that the EBV-encoded miRNAs derived from BamHI-A rightward transcripts (miR-BARTs) are abundantly expressed. The important roles of miR-BARTs in cancer development have been reported extensively. In the present study, we identified multiple putative binding sites of miR-BART5-5p, BART7-3p, BART9-3p and BART14-3p on the 3'-UTR of a critical DNA double-strand break (DSB) repair gene, Ataxia-Telangiectasia-Mutant (ATM). Notably, the expression of these 4 miR-BARTs represented more than 10% of all EBV-encoded miRNAs in NPC cells while downregulation of ATM expression was observed in our local primary NPC samples in both qRT-PCR and immunohistochemical (IHC) staining analysis. In addition, the abilities of miR-BARTs to downregulate ATM expression were demonstrated in the transient transfection experiments. By manipulating the miR-BARTs expression in epithelial cell lines, we further revealed that these four viral miRNAs could inhibit both ionizing radiation (IR)-induced ATM kinase activity and BZLF1-induced viral lytic reactivation. In conclusion, our findings suggest that miR-BART5-5p, BART7-3p, BART9-3p and BART14-3p work co-operatively to modulate DNA damage response and to maintain viral latency, contributing to the NPC tumorigenesis. Acknowledgement: Theme-based Research Scheme (T12-401/13-R) and GRF (14104415 and 14138016), Research Grant Council, Hong Kong.
Citation Format: Raymond W. Lung, Po-Man Hau, Joanna H. Tong, Ka-Hei Lam, Anthony W. Chan, Kevin Y. Yip, George S. Tsao, Kwok-Wai Lo, Ka-Fai To. Epstein-Barr virus-encoded miRNAs target ATM-mediated response in nasopharyngeal carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 482.
Abstract Integrins are adhesion molecules that mediate mechanical and chemical signal transduction pathways to support cell survival and proliferation. Dysregulated integrin signaling empowers tumor ...cells to drive oncogenic stemness functions, including tumor initiation, epithelial plasticity, metastatic reactivation, and resistance to therapies. However, the interplay between cancer stemness and integrin signaling in hepatocellular carcinoma (HCC) remains poorly understood. HCC cells marked by CD133 represent an important functional subset of HCC tumors, displaying a dedifferentiated status with stem cell traits. In this study, transcriptome profiling reveals specific downregulation of integrin α family genes and integrin signaling in ‘HCC’ CD133+ cells isolated from NRAS+AKT-driven HCC, but not epithelial-specific ‘normal’ CD133+ cells isolated from regenerating liver. Of note, one of the most differentially upregulated genes identified in CD133+ HCC cell profiling, microtubule-associated protein MAP2, demonstrates the ability to suppress integrin expression. MAP2 overexpression is frequently observed in HCC and correlates with aggressive clinical and stemness features, including survival, tumor stage, and stemness signatures. Epigenetic modifications by H3K27Ac contribute to MAP2 upregulation. Functionally, MAP2 promotes cancer stemness and cell invasion, and confers resistance to the targeted therapy sorafenib. Mechanistically, the inhibition of collagen-binding integrin α subunits by MAP2 subsequently ablates integrin β1-mediated cell adhesion and FAK signaling. Estramustine Phosphate (EMP), previously reported to inhibit the interaction of MAP2 with actin filaments, attains a synergistic effect in suppressing tumor initiation and growth of HCC cell lines, HCC patient-derived organoids and NRAS+AKT HCC mouse model when used in combination with sorafenib. In summary, MAP2 inhibition may represent a potential novel therapy for HCC by targeting its cancer stemness roots and altering integrin signaling. Ongoing work is focused on the study of MAP2 regulation of integrin signaling and cell behaviours in the maintenance of a more stemness state in HCC. Citation Format: Ut Kei Lou, Ka-Hei Lam, Huajian Yu, Jia Jian Loh, Ki-Fong Man, Lei Zhou, Yuan Gao, Tin-Lok Wong, Cheng-Han Yu, Stephanie Ma. Microtubule-associated protein MAP2 promotes drug resistance and cancer stemness in hepatocellular carcinoma through integrin dysregulation abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5447.
Oridonin is one of the ent-kaurane diterpenes that have been studied extensively for various bioactivities. In an effort to expand natural scaffold-based library as anticancer agents, we have ...designed and synthesised a number of novel oridonin derivatives and evaluated their bioactivities on a panel of human cancer cell lines (HCT116, A375, MCF-7, HepG2, and A549). Compound 4b bearing a 4-fluorophenyl moiety was found to be the most active compound with an IC50 value of 0.3 μM against MCF-7 cells, which was 7.4-fold more active than oridonin. This study could provide some insightful information for further synthesis of oridonin derivatives as anticancer agents.
Full text
Available for:
BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
Abstract
Nasopharyngeal carcinoma (NPC) is an aggressive epithelial malignancy and is endemic in southern China and Southeast Asia. It is well-known to be associated with Epstein-Barr virus (EBV) ...infection. The miRNAs derived from EBV BamH1-A rightward transcripts (miR-BARTs) are abundantly expressed in NPC and have been suggested that can contribute to cancer development by regulating several gene expression. In this study, we established comprehensive expression profile of miRNAs in an EBV positive NPC cell line and 5 xenografts by small RNA sequencing. By using the prediction algorithm of miRanda and RNAhybrid, in silico analysis identified that several abundantly expressed miRNAs from viral and cellular genomes could negatively regulate BRCA1 expression via the 3' untranslated region (3'UTR). Notably, the regulatory role of miR-BART17-5p, miR-BART19-3p, miR182-5p on endogenous BRCA1 expression was demonstrated by transient transfection assays in HeLa cells and the direct recognitions were verified by luciferase reporter assays, while the downregulation of BRCA1 in primary NPCs was substantiated in the immunohistochemical (IHC) staining in a cohort of 61 histologically normal nasopharyngeal (NP) and 37 primary NPC cases (p<0.001). Taken togethher, we showed that the highly expressed miRNAs could work co-operatively to modulate BRCA1 activity. It has been reported that BRCA1 deficient tumor cells are defective in repairing the DNA double-strand breaks (DSBs) via error-free homologous recombination (HR). The impaired DSB repair by EBV latent infection may induce genome instability during NPC tumorigenesis and also contribute to sensitizing the tumor cells to ionizing radiation and DNA-damaging agent treatments.
Acknowledgement:
Theme-based Research Scheme (T12-401/13-R) and GRF (14104415, 14138016), Research Grant Council, Hong Kong
Citation Format: Ka-Hei Lam, Raymond Wai-Ming Lung, Pok-Man Hau, Kevin Yuk-Lap Yip, George Sai-Wah Tsao, Ken Hung-On Yu, Joanna Hung-Man Tong, Kwok-Wai Lo, Ka-Fai To. Epstein-Barr virus-encoded microRNAs regulate the expression of BRCA1 in nasopharyngeal carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2462.
PDF
