Opposing tumor-cell-intrinsic and -extrinsic roles of the IRF1 transcription factor in antitumor immunity.

Type I interferon (IFN-I) and IFN-γ foster antitumor immunity by facilitating T cell responses. Paradoxically, IFNs may promote T cell exhaustion by activating immune checkpoints. The downstream regulators of these disparate responses are incompletely understood. Here, we describe how interferon regulatory factor 1 (IRF1) orchestrates these opposing effects of IFNs. IRF1 expression in tumor cells blocks Toll-like receptor- and IFN-I-dependent host antitumor immunity by preventing interferon-stimulated gene (ISG) and effector programs in immune cells. In contrast, expression of IRF1 in the host is required for antitumor immunity. Mechanistically, IRF1 binds distinctly or together with STAT1 at promoters of immunosuppressive but not immunostimulatory ISGs in tumor cells. Overexpression of programmed cell death ligand 1 (PD-L1) in Irf1-/- tumors only partially restores tumor growth, suggesting multifactorial effects of IRF1 on antitumor immunity. Thus, we identify that IRF1 expression in tumor cells opposes host IFN-I- and IRF1-dependent antitumor immunity to facilitate immune escape and tumor growth.

Alternative splicing of a chromatin modifier alters the transcriptional regulatory programs of stem cell maintenance and neuronal differentiation.

Development of embryonic stem cells (ESCs) into neurons requires intricate regulation of transcription, splicing, and translation, but how these processes interconnect is not understood. We found that polypyrimidine tract binding protein 1 (PTBP1) controls splicing of DPF2, a subunit of BRG1/BRM-associated factor (BAF) chromatin remodeling complexes. Dpf2 exon 7 splicing is inhibited by PTBP1 to produce the DPF2-S isoform early in development. During neuronal differentiation, loss of PTBP1 allows exon 7 inclusion and DPF2-L expression. Different cellular phenotypes and gene expression programs were induced by these alternative DPF2 isoforms. We identified chromatin binding sites enriched for each DPF2 isoform, as well as sites bound by both. In ESC, DPF2-S preferential sites were bound by pluripotency factors. In neuronal progenitors, DPF2-S sites were bound by nuclear factor I (NFI), while DPF2-L sites were bound by CCCTC-binding factor (CTCF). DPF2-S sites exhibited enhancer modifications, while DPF2-L sites showed promoter modifications. Thus, alternative splicing redirects BAF complex targeting to impact chromatin organization during neuronal development.

The transcription factor NF-κB orchestrates nucleosome remodeling during the primary response to Toll-like receptor 4 signaling.

Inducible nucleosome remodeling at hundreds of latent enhancers and several promoters shapes the transcriptional response to Toll-like receptor 4 (TLR4) signaling in macrophages. We aimed to define the identities of the transcription factors that promote TLR-induced remodeling. An analysis strategy based on ATAC-seq and single-cell ATAC-seq that enriched for genomic regions most likely to undergo remodeling revealed that the transcription factor nuclear factor κB (NF-κB) bound to all high-confidence peaks marking remodeling during the primary response to the TLR4 ligand, lipid A. Deletion of NF-κB subunits RelA and c-Rel resulted in the loss of remodeling at high-confidence ATAC-seq peaks, and CRISPR-Cas9 mutagenesis of NF-κB-binding motifs impaired remodeling. Remodeling selectivity at defined regions was conferred by collaboration with other inducible factors, including IRF3- and MAP-kinase-induced factors. Thus, NF-κB is unique among TLR4-activated transcription factors in its broad contribution to inducible nucleosome remodeling, alongside its ability to activate poised enhancers and promoters assembled into open chromatin.

Aster-B-dependent estradiol synthesis protects female mice from diet-induced obesity.

Aster proteins mediate the nonvesicular transport of cholesterol from the plasma membrane (PM) to the endoplasmic reticulum (ER). However, the importance of nonvesicular sterol movement for physiology and pathophysiology in various tissues is incompletely understood. Here we show that loss of Aster-B leads to diet-induced obesity in female but not in male mice, and that this sex difference is abolished by ovariectomy. We further demonstrate that Aster-B deficiency impairs nonvesicular cholesterol transport from the PM to the ER in ovaries in vivo, leading to hypogonadism and reduced estradiol synthesis. Female Aster-B-deficient mice exhibit reduced locomotor activity and energy expenditure, consistent with established effects of estrogens on systemic metabolism. Administration of exogenous estradiol ameliorates the diet-induced obesity phenotype of Aster-B-deficient female mice. These findings highlight the key role of Aster-B-dependent nonvesicular cholesterol transport in regulating estradiol production and protecting females from obesity.

Safety evaluation of combination treatment of drug-eluting bead transarterial chemoembolization and immune checkpoint inhibitors for hepatocellular carcinoma: An increased risk of liver abscess with treatment interval less than one month.

PURPOSE: To analyze the safety of combination treatment comprising drug-eluting bead transarterial chemoembolization (DEB-TACE) and immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC). METHOD: In total, 208 HCC patients receiving DEB-TACE were enrolled for this retrospective single-institution study. Among them, 50 patients who received ICIs at an interval less than one month from DEB-TACE were categorized into the DEB-ICI group; the remaining 158 patients were categorized into the DEB group. Albumin-bilirubin (ALBI) score before and at three months after DEB-TACE were recorded to evaluate liver function changes. Adverse events within three months after DEB-TACE were considered TACE-related and were compared between the two groups. RESULTS: The DEB-ICI group had significantly higher incidence of liver abscess than the DEB group (14.0 % versus 5.1 %, p-value = 0.0337). No significant difference in the other TACE-related adverse events and change of ALBI score between the groups. Univariate logistic regression confirmed that combination with ICIs was an independent risk factor for liver abscess after DEB-TACE (odds ratio = 3.0523, 95 % confidence interval: 1.0474-8.8947, p-value = 0.0409); other parameters including subjective angiographic chemoembolization endpoint scale and combined targeted therapy were nonsignificant risk factors in this study population. In the DEB-ICI group, patients who received ICIs before DEB-TACE exhibited a trend toward liver abscess formation compared with those who received DEB-TACE before ICIs (23.8 % versus 6.9 %, p-value = 0.0922). CONCLUSIONS: Combination treatment involving DEB-TACE and ICIs at an interval less than one month increased the risk of liver abscess after DEB-TACE. Greater caution is therefore warranted for HCC patients who receive ICIs and DEB-TACE with this short interval.

Advancing breast cancer subtyping: optimizing immunohistochemical staining classification with insights from real-world Taiwanese data.

Gene expression signatures provide valuable information to guide postoperative treatment in breast cancer (BC) patients. However, genetic tests are prohibitively expensive for the majority of BC patients. Immunohistochemical staining (IHC) subtype classification system has been widely used for treatment guideline and is affordable to most BC patients. We aimed to revise immunohistochemical staining (IHC) subtyping to better match gene expression-based Prediction Analysis of Microarray 50 (PAM50) subtyping. Real world data of 372 BC patients were recruited in the Tri-Service General Hospital between Jan 2019 and Dec 2021. Clinical pathological information, blood, twelve pathological tissue slide samples, and fresh surgical tumor specimens were collected to examine IHC and PAM50. Current IHC subtyping (cIHC) tends to misclassify PAM50-based luminal A (lum A) to luminal B (lum B) by 35.81%, PAM50-lum B to PAM50-lum A by 9.09%, PAM50-Her2-enriched to lum B by 61.11%, PAM50-based Her2-enriched to lum B by 61.11%, and PAM50-based basal-like to lum B by 33.33%. We used random forest to identify estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (Her2), and Ki-67 status as the best indicators for revised IHC subtyping (rIHC4) and revised the classification rules by stratified analysis and prediction efficacy. rIHC4 increased the concordance rate for PAM50 subtypes from 68.3% to 74.7%. Both sensitivity and precision increased in most rIHC4 subtypes. Sensitivity increased from 33.3% to 87.4% in the Her2-enriched subtype; precision increased more evidently in the basal-like and lum B subtypes, from 71.4% to 83.3% and 57% to 65.1%, respectively. Our rIHC4 subtyping improved consistency with the PAM50 subtype, which could improve clinical management of BC patients without increasing medical expense.

Mitral valve prolapse and physical performance in Asian military males: The CHIEF Heart study.

The impact of mitral valve prolapse (MVP) and mitral regurgitation (MR) on physical performance has not been examined. Of 1,808 physically fit Asian military males, we compared the physical fitness between 62 subjects with MVP (MVP(+)) and 1,311 age- and anthropometrics-matched controls from the 1,746 participants without MVP (MVP(-)). MVP and MR grade were defined based on the American Society of Echocardiography criteria. Aerobic endurance capacity was evaluated by a 3000-m run and muscular endurance capacity was separately evaluated by 2-min sit-ups and 2-min push-ups. Analysis of covariance was used to determine the difference between groups. As compared to the MVP(-), the MVP(+) completed the 3000-m run test faster (839.2 ± 65.3 sec vs. 866.6 ± 86.8 sec, p = 0.019), but did fewer push-ups (41.3 ± 3.92 vs. 48.0 ± 10.1, p = 0.02) and similar sit-ups within 2 min. Of the MVP(+), those with any MR (trivial, mild or moderate) completed the 3000-m run test faster than those without MR (830.6 ± 61.7 sec vs. 877.2 ± 61.7 sec, p = 0.02). Our findings suggest that in physically active Asian military males, the MVP(+) may have greater aerobic endurance capacity but lower muscular endurance capacity than the MVP(-). The presence of MR may play a role for the MVP(+) to have greater aerobic endurance capacity.

The Risk of Breast Cancer between Western and Mediterranean Dietary Patterns.

Breast cancer is a significant public health problem globally and prevention strategies have become of great interest as its incidence rises. Exploring the connection between dietary patterns and the reduction of breast cancer risk is considered a promising approach. High levels of fiber, phytochemicals, a good antioxidant profile, and a composition of advantageous fatty acids are characteristics of healthy dietary programs such as the Mediterranean diet. This review summarized and discussed the active compounds that are considered important in preventing breast cancer, including dietary components from recent related reports. These include polyunsaturated fatty acids, fiber, phytochemicals, and alcohol. Although the exact mechanism for preventing breast cancer using these dietary factors is not well understood, the combination of all the elements in a healthy diet plays a role in reducing breast cancer risk. Considering the elevated probability of breast cancer relapse and mortality, it is crucial to investigate the correlation between a nutritious dietary pattern and breast cancer, while identifying bioactive components that have the potential to mitigate the risk of breast cancer incidence.

Hepatic GATA4 regulates cholesterol and triglyceride homeostasis in collaboration with LXRs.

GATA4 is a transcription factor known for its crucial role in the development of many tissues, including the liver; however, its role in adult liver metabolism is unknown. Here, using high-throughput sequencing technologies, we identified GATA4 as a transcriptional regulator of metabolism in the liver. GATA4 expression is elevated in response to refeeding, and its occupancy is increased at enhancers of genes linked to fatty acid and lipoprotein metabolism. Knocking out GATA4 in the adult liver (Gata4LKO) decreased transcriptional activity at GATA4 binding sites, especially during feeding. Gata4LKO mice have reduced plasma HDL cholesterol and increased liver triglyceride levels. The expression of a panel of GATA4 binding genes involved in hepatic cholesterol export and triglyceride hydrolysis was down-regulated in Gata4LKO mice. We further demonstrate that GATA4 collaborates with LXR nuclear receptors in the liver. GATA4 and LXRs share a number of binding sites, and GATA4 was required for the full transcriptional response to LXR activation. Collectively, these results show that hepatic GATA4 contributes to the transcriptional control of hepatic and systemic lipid homeostasis.

Erythrocyte indices and localized stage II/III periodontitis in military young men and women: CHIEF oral health study.

BACKGROUND: Prior studies have shown an association between generalized periodontitis and anemia in older or undernourished adults. The aim of the study was to examine the associations of erythrocyte indices with localized periodontitis in robust young adults, which has never been reported before. METHODS: The study included 1286 military participants, aged 19-40 years, with regular exercise training in Hualien, Taiwan. Localized periodontitis was grouped to healthy/stage I and stage II/III (n = 803 and 325) in men and (n = 130 and 28) in women according to the 2017 criteria of the world workshop. Systemic inflammation was evaluated by leukocyte counts. Multiple logistic regression analysis with adjustment for age, tobacco smoking status, betel nut chewing status, body mass index and leucocyte counts were used to determine the associations. RESULTS: Greater mean corpuscular volume in young men [odds ratio (OR) and 95% confidence intervals 1.03 (1.01-1.06)], and greater hematocrit and hemoglobin levels in young women were associated with a higher risk of localized stage II/III periodontitis [OR: 1.17 (1.02-1.34) and 1.60 (1.06-2.41), respectively]. However, there were no associations for erythrocyte counts. CONCLUSIONS: The localized stage II/III periodontitis risk increased with greater erythrocyte indices in robust young adults. This finding could be explained in part by that localized periodontitis may promote physical stress, possibly resulting in an increase of erythrocyte indices. On the other side, greater physical fitness associated with a lower risk of periodontitis may consume iron storage in the body, leading to exercise-induced anemia or smaller erythrocyte volume.

The impact of frailty on breast cancer outcomes: evidence from analysis of the Nationwide Inpatient Sample, 2005-2018.

The aims of the present study were to examine whether and how frailty impacts the outcomes of breast cancer. Data of women with breast cancer hospitalized during 2005 and 2018 were extracted from the US Nationwide Inpatient Sample (NIS) database. Frailty was identified using a novel algorithm, Hospital Frailty Risk Score (HFRS). Propensity-score (PS) matching was utilized to balance the baseline characteristics between frail and non-frail groups. In-hospital mortality, unfavorable discharge, prolonged length of stay (LOS), and total hospital cost were compared using univariate and multivariable logistic regression analyses. A total of 19,522 patients with metastatic (frailty n = 9,906; no frailty n = 9,716) and 135,200 with non-metastatic breast cancer (frailty n = 30,235; no frailty n = 104,965) were included. After adjustment, frailty was significantly and independently associated with higher risk for in-hospital mortality, unfavorable discharge, prolonged LOS, and greater hospital cost in both metastatic and non-metastatic diseases, in which the impacts of frailty was greater in women with non-metastatic disease. In stratified analysis, frailty had the greatest impact on in-hospital mortality among women had had non-metastatic disease and aged <50 years (aOR = 3.88; 95% CI: 1.95-7.73). In conclusion, frailty is associated with worse outcomes in women with breast cancer, and the effects are greater in non-metastatic disease and younger patients.

Combined Nissen Fundoplication and Single Anastomosis Sleeve Ileal Bypass (N-SASI) as a Practical Modality of Bariatric Surgery (Video Report).

Sleeve gastrectomy is one of the most common bariatric procedures because of its simplicity and effectiveness. Gastro-esophageal reflux disease (GERD) symptoms and weight regain after SG are common issues. Roux-en-Y gastric bypass (RYGB) is currently the most promising approach to achieve satisfying weight loss and GERD remission; however, remnant gastric cancer is still a major concern for patients. We present a video case that individualized procedure of Nissen fundoplication, and SASI bypass (N-SASI) was designed and applied to the patient with class III obesity and severe GERD. This is a 37-year-old man with obesity (BMI: 41.8 kg/m2, categorized as class III obesity) and associated disease of stage 1 hypertension, hyperlipidemia, obstructive sleep apnea syndrome, and non-alcoholic steatohepatitis as well as severe symptoms of GERD. Esophageal-gastro-duodenal scope revealed GERD grade C, hiatal hernia, and duodenal ulcer. He refused RYGB recommended initially due to serious concern about remnant gastric cancer. We therefore performed Nissen fundoplication for his GERD symptoms and adapted SASI bypass instead of RYGB as the individualized bariatric surgery to achieve the optimal surgical outcome. The postoperative course was smooth, and the patient was discharged on postoperative day 8.

CRNDE-h transcript/miR-136-5p axis regulates interleukin enhancer binding factor 2 expression to promote hepatocellular carcinoma cell proliferation.

AIMS: Hepatocellular carcinoma (HCC) is a primary malignancy of the hepatocyte. Interleukin enhancer binding factor 2 (ILF2) plays a role in the development of HCC. However, the regulatory mechanisms of ILF2 expression in HCC remain unclear. In this study, we aimed to identify ILF2-targeting microRNAs (miRNAs) and to explore how they affect ILF2 expression in HCC. MAIN METHODS: The tissue specimens were collected from 25 HCC patients. The underlying regulatory mechanism of ILF2 expression in HCC progression was determined using luciferase reporter assay, quantitative real-time PCR, Western blotting, and BrdU incorporation assay. KEY FINDINGS: Of predicted miRNA candidates (miR-122-5p, miR-425-5p, miR-136-5p, miR-7-5p, miR-421 and miR-543), a statistically significant inverse correlation by linear correlation analysis was observed between miR-136-5p and ILF2 mRNA expressions in patients with HCC (r = -0.627, P < 0.001). Further analysis demonstrated that ILF2 was directly regulated by miR-136-5p. In addition, we showed that long noncoding RNA colorectal neoplasia differentially expressed-h (lncRNA CRNDE-h) transcript expression was significantly up-regulated in HCC, and a miR-136-5p binding site was newly found in the lncRNA CRNDE-h transcript sequence using IntaRNA tool. In terms of mechanism, highly-expressed lncRNA CRNDE-h transcript can sponge miR-136-5p, thereby preventing it from interacting with target ILF2 mRNA while promoting the proliferation of HCC cells. SIGNIFICANCE: The lncRNA CRNDE-h/miR-136-5p/ILF2 axis plays a significant regulatory role in HCC progression, which may partly explain the pathogenic mechanisms of HCC and may provide promising potential targets for the diagnosis, treatment, and prognosis of HCC.

Activating an adaptive immune response from a hydrogel scaffold imparts regenerative wound healing.

Microporous annealed particle (MAP) scaffolds are flowable, in situ crosslinked, microporous scaffolds composed of microgel building blocks and were previously shown to accelerate wound healing. To promote more extensive tissue ingrowth before scaffold degradation, we aimed to slow MAP degradation by switching the chirality of the crosslinking peptides from L- to D-amino acids. Unexpectedly, despite showing the predicted slower enzymatic degradation in vitro, D-peptide crosslinked MAP hydrogel (D-MAP) hastened material degradation in vivo and imparted significant tissue regeneration to healed cutaneous wounds, including increased tensile strength and hair neogenesis. MAP scaffolds recruit IL-33 type 2 myeloid cells, which is amplified in the presence of D-peptides. Remarkably, D-MAP elicited significant antigen-specific immunity against the D-chiral peptides, and an intact adaptive immune system was required for the hydrogel-induced skin regeneration. These findings demonstrate that the generation of an adaptive immune response from a biomaterial is sufficient to induce cutaneous regenerative healing despite faster scaffold degradation.

Interferon-mediated reprogramming of membrane cholesterol to evade bacterial toxins.

Plasma membranes of animal cells are enriched for cholesterol. Cholesterol-dependent cytolysins (CDCs) are pore-forming toxins secreted by bacteria that target membrane cholesterol for their effector function. Phagocytes are essential for clearance of CDC-producing bacteria; however, the mechanisms by which these cells evade the deleterious effects of CDCs are largely unknown. Here, we report that interferon (IFN) signals convey resistance to CDC-induced pores on macrophages and neutrophils. We traced IFN-mediated resistance to CDCs to the rapid modulation of a specific pool of cholesterol in the plasma membrane of macrophages without changes to total cholesterol levels. Resistance to CDC-induced pore formation requires the production of the oxysterol 25-hydroxycholesterol (25HC), inhibition of cholesterol synthesis and redistribution of cholesterol to an esterified cholesterol pool. Accordingly, blocking the ability of IFN to reprogram cholesterol metabolism abrogates cellular protection and renders mice more susceptible to CDC-induced tissue damage. These studies illuminate targeted regulation of membrane cholesterol content as a host defense strategy.

Collaborative interactions of heterogenous ribonucleoproteins contribute to transcriptional regulation of sterol metabolism in mice.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are a group of functionally versatile proteins that play critical roles in the biogenesis, cellular localization and transport of RNA. Here, we outline a role for hnRNPs in gene regulatory circuits controlling sterol homeostasis. Specifically, we find that tissue-selective loss of the conserved hnRNP RALY enriches for metabolic pathways. Liver-specific deletion of RALY alters hepatic lipid content and serum cholesterol level. In vivo interrogation of chromatin architecture and genome-wide RALY-binding pattern reveal insights into its cooperative interactions and mode of action in regulating cholesterogenesis. Interestingly, we find that RALY binds the promoter region of the master metabolic regulator Srebp2 and show that it directly interacts with coactivator Nuclear Transcription Factor Y (NFY) to influence cholesterogenic gene expression. Our work offers insights into mechanisms orchestrating selective promoter activation in metabolic control and a model by which hnRNPs can impact health and disease states.

Single cell analysis reveals immune cell-adipocyte crosstalk regulating the transcription of thermogenic adipocytes.

Immune cells are vital constituents of the adipose microenvironment that influence both local and systemic lipid metabolism. Mice lacking IL10 have enhanced thermogenesis, but the roles of specific cell types in the metabolic response to IL10 remain to be defined. We demonstrate here that selective loss of IL10 receptor α in adipocytes recapitulates the beneficial effects of global IL10 deletion, and that local crosstalk between IL10-producing immune cells and adipocytes is a determinant of thermogenesis and systemic energy balance. Single Nuclei Adipocyte RNA-sequencing (SNAP-seq) of subcutaneous adipose tissue defined a metabolically-active mature adipocyte subtype characterized by robust expression of genes involved in thermogenesis whose transcriptome was selectively responsive to IL10Rα deletion. Furthermore, single-cell transcriptomic analysis of adipose stromal populations identified lymphocytes as a key source of IL10 production in response to thermogenic stimuli. These findings implicate adaptive immune cell-adipocyte communication in the maintenance of adipose subtype identity and function.

Enhanced In Vivo Delivery of Stem Cells using Microporous Annealed Particle Scaffolds.

Delivery to the proper tissue compartment is a major obstacle hampering the potential of cellular therapeutics for medical conditions. Delivery of cells within biomaterials may improve localization, but traditional and newer void-forming hydrogels must be made in advance with cells being added into the scaffold during the manufacturing process. Injectable, in situ cross-linking microporous scaffolds are recently developed that demonstrate a remarkable ability to provide a matrix for cellular proliferation and growth in vitro in three dimensions. The ability of these scaffolds to deliver cells in vivo is currently unknown. Herein, it is shown that mesenchymal stem cells (MSCs) can be co-injected locally with microparticle scaffolds assembled in situ immediately following injection. MSC delivery within a microporous scaffold enhances MSC retention subcutaneously when compared to cell delivery alone or delivery within traditional in situ cross-linked nanoporous hydrogels. After two weeks, endothelial cells forming blood vessels are recruited to the scaffold and cells retaining the MSC marker CD29 remain viable within the scaffold. These findings highlight the utility of this approach in achieving localized delivery of stem cells through an injectable porous matrix while limiting obstacles of introducing cells within the scaffold manufacturing process.

IL-10 Signaling Remodels Adipose Chromatin Architecture to Limit Thermogenesis and Energy Expenditure.

Signaling pathways that promote adipose tissue thermogenesis are well characterized, but the limiters of energy expenditure are largely unknown. Here, we show that ablation of the anti-inflammatory cytokine IL-10 improves insulin sensitivity, protects against diet-induced obesity, and elicits the browning of white adipose tissue. Mechanistic studies define bone marrow cells as the source of the IL-10 signal and adipocytes as the target cell type mediating these effects. IL-10 receptor alpha is highly enriched in mature adipocytes and is induced in response to differentiation, obesity, and aging. Assay for transposase-accessible chromatin sequencing (ATAC-seq), ChIP-seq, and RNA-seq reveal that IL-10 represses the transcription of thermogenic genes in adipocytes by altering chromatin accessibility and inhibiting ATF and C/EBPß recruitment to key enhancer regions. These findings expand our understanding of the relationship between inflammatory signaling pathways and adipose tissue function and provide insight into the physiological control of thermogenesis that could inform future therapy.

HCV core inhibits hepatocellular carcinoma cell replicative senescence through downregulating microRNA-138 expression.

Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). HCV core protein is considered as a positive regulator of telomerase activity. In this study, we focused on the deregulated microRNA-138 (miR-138) in HCV-associated HCC. Differential expression of miR-138 was determined by TaqMan quantitative real-time PCR. The target gene of miR-138 was verified by luciferase reporter assay, quantitative real-time PCR, and Western blotting. Moreover, three assays based on telomerase activity, cell proliferation, and senescence-associated ß-galactosidase activity were performed. The correlation analysis revealed a significantly negative correlation between miR-138 and telomerase reverse transcriptase (TERT) mRNA expression in HCC. Further, we showed that mature HCV core protein of 173 amino acids, but not full-length form of 191 amino acids, suppressed miR-138 expression. TERT was verified as a direct target of miR-138 in HCC cells. Furthermore, TERT-targeting miR-138 supplementation can prevent HCV core protein from repressing HCC cell replicative senescence. Collectively, HCV core protein can enhance TERT protein expression through downregulating TERT-targeting miR-138 expression, which in turn inhibits HCC cell replicative senescence. This study may further help our understanding on the pathogenic mechanisms of HCV core protein in HCV-associated HCC development. KEY MESSAGE: miR-138 is downregulated in HCV-associated HCC. Mature HCV core protein plays a pathogenic role in suppressing miR-138 expression. Telomerase reverse transcriptase represents a direct target of miR-138 in HCC cells. miR-138 promotes HCC cell senescence, suggesting potential for HCC treatment.