International Journal of Experimental Pathology最新文献

{"title":"Renal protective roles of macrophage matrix metalloproteinase-12 in mice with obstructed kidneys","authors":"Shunichiro Hanai,&nbsp;Daiki Nakagomi,&nbsp;Kotaro Suzuki,&nbsp;Hiroshi Nakajima,&nbsp;Fumihiko Furuya","doi":"10.1111/iep.12516","DOIUrl":"10.1111/iep.12516","url":null,"abstract":"<p>Matrix metalloproteinase (MMP)-12 has been reported to have diverse functions, including regulation of immune reactions and anti-inflammatory effects, but the potential roles of MMP-12 in kidney injury have not been fully elucidated. This study aimed to determine whether MMP-12 contributes to tubulointerstitial injury in a unilateral ureteric obstruction (UUO) model. MMP-12-deficient (MMP-12^−/−) mice and C57BL/6J mice as controls (MMP-12^+/+) were subjected to UUO and analysed 7 days after UUO. To analyse the functions of MMP-12 on monocytes/macrophages, we generated MMP-12-deficient, irradiated, chimeric mice (BM-MMP-12^−/−) and performed UUO. Bone marrow-derived macrophages (BMDMs) were isolated from both groups of mice and used for investigations. MMP-12^−/− mice showed exacerbation of macrophage accumulation and interstitial fibrosis in the UUO-kidney compared with control mice. BM-MMP-12^−/− mice also showed exacerbation of kidney injury. UUO induced accumulation of Ly6C⁺ macrophages in MMP-12^−/− mice compared with control mice. Increases in inflammatory cytokine (tumour necrosis factor α, interleukin [IL]-1β, IL-6) levels from BMDMs after lipopolysaccharide stimulation were higher in MMP-12^−/− mice than in MMP-12^+/+ mice. MMP-12 may play protective roles against kidney injury by UUO in mice, decreasing inflammatory cytokines from BMDMs and macrophage accumulation.</p>","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":"105 5","pages":"193-201"},"PeriodicalIF":1.8,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zinc transporter ZnT5 is associated with epithelial mesenchymal transition via SMAD1 in breast cancer","authors":"Erina Iwabuchi,&nbsp;Yasuhiro Miki,&nbsp;Junyao Xu,&nbsp;Ayako Kanai,&nbsp;Takanori Ishida,&nbsp;Hironobu Sasano,&nbsp;Takashi Suzuki","doi":"10.1111/iep.12515","DOIUrl":"10.1111/iep.12515","url":null,"abstract":"<p>Zinc levels in breast cancer tissues have been reported to be higher than those in normal tissues. In addition, the expression levels of zinc transporters, including ZnT5 and ZnT6, are reportedly higher in breast cancer than in normal breast tissues. ZnT5 and ZnT6 also contribute to heterodimer formation and are involved in several biological functions. However, the functions of ZnT5 and ZnT6 heterodimers in breast cancer remain unknown. Therefore, we first investigated the immunolocalization of ZnT5 and ZnT6 in pathological breast cancer specimens and in MCF-7 and T-47D breast cancer cells. Next, we used small interfering RNA to assess cell viability and migration in ZnT5 knockdown MCF-7 and T-47D cells. Immunohistochemical analysis showed that the number of ZnT5-positive breast cancer cells was inversely correlated with the pathologic N factor status. ZnT5 knockdown had no effect on cell viability in the presence of 100 μM ZnCl₂ in MCF-7 and T-47D cells. In a wound healing assay, 100 μM ZnCl₂ treatment inhibited cell migration of MCF-7 and T-47D cells, whereas ZnT5 knockdown promoted cell migration, decreased E-cadherin expression and increased vimentin, slug and matrix metalloproteinase 9 expression. Antibody arrays showed that ZnT5 knockdown increased the expression of SMAD1, and that dorsomorphin treatment inhibited the promotion of migratory ability induced by ZnT5 knockdown. The results of this study revealed that both ZnT5 may be involved in less aggressive breast cancer subtypes, possibly through inhibition of cell migration.</p>","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":"105 5","pages":"184-192"},"PeriodicalIF":1.8,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/iep.12515","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Feline hypertrophic cardiomyopathy: Does the microRNA-mRNA regulatory network contribute to heart sarcomeric protein remodelling?","authors":"Gabriella Guelfi,&nbsp;Noemi Venanzi,&nbsp;Camilla Capaccia,&nbsp;Valentina Stefanetti,&nbsp;Chiara Brachelente,&nbsp;Monica Sforna,&nbsp;Francesco Porciello,&nbsp;Elvio Lepri","doi":"10.1111/iep.12514","DOIUrl":"10.1111/iep.12514","url":null,"abstract":"<p>Feline primary hypertrophic cardiomyopathy (HCM) is an intrinsic myocardial disease characterized by concentric hypertrophy of the left ventricle. In the present study, we investigated the microRNA-mRNA regulatory network in feline myocardial tissue affected by primary (HCMI) and secondary HCM (HCMII). MRNA expression levels of sarcomeric genes, including, <i>TNNT2</i>, <i>TNNI3</i>, <i>MYH7</i>, <i>MYBPC3</i>, <i>TPM1</i> and <i>ACTC1</i> were assessed in the FFPE myocardial tissues. FFPE tissues from healthy cats were sequenced by the NGS, to explore, in the entire non-deposited miRNome, the expression level of microRNAs targeting the complementary sequences of selected sarcomeric mRNAs. The sarcomeric genes <i>TNNT2</i>, <i>MYH7</i>, <i>MYBPC3</i> and <i>TPM1</i> showed a statistically significant upregulation in HCMI compared to HCMII (<i>p</i> &lt; .01), except <i>ACTC1</i> which was downregulated (<i>p</i> &lt; .01); <i>TNNI3</i> showed no statistically significant difference. In HCMII miR-122-5p, miR-338-3p, miR-484, miR-370-3p, miR-92b-3p, miR-375 and miR-370-3p showed a significant upregulation (<i>p</i> &lt; .01) compared to control. The exception was miR-30a-5p which showed downregulation. Worthy of note is the 4-fold higher expression of miR-370-3p, a key regulator of <i>MYBPC3</i>, in HMCI compared to HMCII. This research does not solve the aetiological mystery of HCM, but it may help to find a way to help diagnose and define the prognosis of HCM in cats.</p>","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":"105 5","pages":"170-183"},"PeriodicalIF":1.8,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/iep.12514","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"British Society for Matrix Biology Spring Meeting 2024: The Dynamic matrix—Mechanics, Ageing and Repair","authors":"","doi":"10.1111/iep.12512","DOIUrl":"10.1111/iep.12512","url":null,"abstract":"","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":"105 4","pages":"A1-A23"},"PeriodicalIF":1.8,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141748155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GABRP inhibits the progression of oesophageal cancer by regulating CFTR: Integrating bioinformatics analysis and experimental validation","authors":"Jingzhi Zhang,&nbsp;Xue Liu,&nbsp;Ling Zeng,&nbsp;Ying Hu","doi":"10.1111/iep.12513","DOIUrl":"10.1111/iep.12513","url":null,"abstract":"<p>Oesophageal cancer (EC) is a malignancy which accounts for a substantial number of cancer-related deaths worldwide. The molecular mechanisms underlying the pathogenesis of EC have not been fully elucidated. GSE17351 and GSE20347 data sets from the Gene Expression Omnibus (GEO) database were employed to screen differentially expressed genes (DEGs). Reverse transcription quantitative PCR (RT-qPCR) was used to examine hub gene expression. ECA-109 and TE-12 cells were transfected using the pcDNA3.1 expression vector encoding <i>GABRP</i>. The cell counting kit-8 (CCK-8), cell scratch and Transwell assays were performed to assess the effect of <i>GABRP</i> on EC cell proliferation, migration and invasion. Epithelial-mesenchymal transition (EMT)-associated protein levels were measured by Western blotting. Subsequently, <i>CFTR</i> was knocked down to verify whether <i>GABRP</i> affected biological events in EC cells by targeting <i>CFTR</i>. Seven hub genes were identified, including <i>GABRP</i>, <i>FLG</i>, <i>ENAH</i>, <i>KLF4</i>, <i>CD24</i>, <i>ABLIM3</i> and <i>ABLIM1</i>, which all could be used as diagnostic biomarkers for EC. The RT-qPCR results indicated that the expression levels of <i>GABRP</i>, <i>FLG</i>, <i>KLF4</i>, <i>CD24</i>, <i>ABLIM3</i> and <i>ABLIM1</i> were downregulated, whereas the expression level of <i>ENAH</i> was upregulated. In vitro functional assays demonstrated that <i>GABRP</i> overexpression suppressed the proliferation, migration, invasion and EMT of EC cells. Mechanistically, <i>GABRP</i> promoted the expression of <i>CFTR</i>, and <i>CFTR</i> knockdown significantly counteracted the influence of <i>GABRP</i> overexpression on biological events in EC cells. Overexpression of <i>GABRP</i> inhibited EC progression by increasing <i>CFTR</i> expression, which might be a new target for EC treatment.</p>","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":"105 4","pages":"118-132"},"PeriodicalIF":1.8,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141579639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “Clinical applications of gene therapy for rare diseases: A review”","authors":"","doi":"10.1111/iep.12505","DOIUrl":"10.1111/iep.12505","url":null,"abstract":"<p>Papaioannou I, Owen JS and Yáñez-Muñoz RJ. Clinical applications of gene therapy for rare diseases: A review. <i>Int J Exp Pathol</i> 2023 Aug;104(4):154–176. doi: 10.1111/iep.12478. Epub 2023 May 13.</p><p>It has been brought to our attention that in paragraph 1 of section 5.3, some details regarding the design of Zolgensma were not accurate. Therefore, the following text was incorrect: “Zolgensma (Onasemnogene Abeparvovec)^196–200 is an AAV-based gene supplementation treatment aimed at directly and permanently restoring <i>SMN1</i> expression with a single dose. The design of the Zolgensma expression cassette is similar to Luxturna (Figure 5), in using the hybrid CMV–Chicken beta actin promoter to drive the expression of <i>SMN1</i> cDNA. To enhance expression, the design incorporates an artificial intron (from SV40) and codon optimization. The sequence of AVXS-101 (the vector for Zolgensma) is proprietary and the exact optimizations are not in the public domain, but the effectiveness of this approach was documented by using a similar AAV9 platform.^201–203 A self-complementary design (Figure 12) was employed, where one of the flanking ITRs was a specially engineered variant to synthesize genome dimers, rather than monomers.²⁰⁴”</p><p>This should have read: “Zolgensma (Onasemnogene Abeparvovec)^196–200 is an AAV-based gene supplementation treatment aimed at directly and permanently restoring SMN protein production with a single dose. The design of the Zolgensma expression cassette is similar to Luxturna (Figure 5) in using the hybrid CMV–Chicken beta-actin promoter to drive the expression of <i>SMN2</i> cDNA, and it includes the bovine growth hormone polyadenylation sequence. To enhance expression, the design incorporates an artificial intron (from SV40). Unusually, the sequence of the <i>SMN2</i> cDNA in Zolgensma was not codon-optimized. The effectiveness of AVXS-101 (the vector for Zolgensma) was corroborated by the work of several other groups using similar self-complementary AAV9-<i>SMN</i> platforms^201–203 (Figure 12), where one of the flanking ITRs was a specially engineered variant to synthesize genome dimers, rather than monomers.²⁰⁴”</p><p>We apologize for this error.</p>","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":"105 3","pages":"114"},"PeriodicalIF":3.0,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/iep.12505","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140922113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Muscle fibre morphometric analysis (MusMA) correlates with muscle function and cardiovascular risk prognosis","authors":"Larisse Longo,&nbsp;Bárbara Jonson Bartikoski,&nbsp;Valessa Emanoele Gabriel de Souza,&nbsp;Fernando Salvati,&nbsp;Carolina Uribe-Cruz,&nbsp;Guido Lenz,&nbsp;Ricardo Machado Xavier,&nbsp;Mário Reis Álvares-da-Silva,&nbsp;Eduardo Cremonese Filippi-Chiela","doi":"10.1111/iep.12504","DOIUrl":"10.1111/iep.12504","url":null,"abstract":"<p>Morphometry of striated muscle fibres is critical for monitoring muscle health and function. Here, we evaluated functional parameters of skeletal and cardiac striated muscle in two experimental models using the Morphometric Analysis of Muscle Fibre tool (MusMA). The collagen-induced arthritis model was used to evaluate the function of skeletal striated muscle and the non-alcoholic fatty liver disease model was used for cardiac striated muscle analysis. After euthanasia, we used haeamatoxylin and eosin stained sections of skeletal and cardiac muscle to perform muscle fibre segmentation and morphometric analysis. Morphometric analysis classified muscle fibres into six subpopulations: normal, regular hypertrophic, irregular hypertrophic, irregular, irregular atrophic and regular atrophic. The percentage of atrophic fibres was associated with lower walking speed (<i>p</i> = 0.009) and lower body weight (<i>p</i> = 0.026), respectively. Fibres categorized as normal were associated with maximum grip strength (<i>p</i> &lt; 0.001) and higher march speed (<i>p</i> &lt; 0.001). In the evaluation of cardiac striated muscle fibres, the percentage of normal cardiomyocytes negatively correlated with cardiovascular risk markers such as the presence of abdominal adipose tissue (<i>p</i> = .003), miR-33a expression (<i>p</i> = .001) and the expression of miR-126 (<i>p</i> = .042) Furthermore, the percentage of atrophic cardiomyocytes correlated significantly with the Castelli risk index II (<i>p</i> = .014). MusMA is a simple and objective tool that allows the screening of striated muscle fibre morphometry, which can complement the diagnosis of muscle diseases while providing functional and prognostic information in basic and clinical research.</p>","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":"105 3","pages":"100-113"},"PeriodicalIF":3.0,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140897872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microfluidics-based EGFR mutation detection and its implication in the resource-limited clinical setting","authors":"Pradnya Joshi,&nbsp;Prachi Gogte,&nbsp;Trupti Pai,&nbsp;Mamta Gurav,&nbsp;Dipika Dhanawade,&nbsp;Nupur Karnik,&nbsp;Gauri Deshpande,&nbsp;Rajiv Kaushal,&nbsp;Omshree Shetty","doi":"10.1111/iep.12503","DOIUrl":"10.1111/iep.12503","url":null,"abstract":"<p>Management of lung cancer today obligates a mutational analysis of the epidermal growth factor receptor (<i>EGFR)</i> gene particularly when Tyrosine Kinase Inhibitor (TKI) therapy is being considered as part of prognostic stratification. This study evaluates the performance of automated microfluidics-based <i>EGFR</i> mutation detection and its significance in clinical diagnostic settings. Formalin-fixed, paraffin-embedded (FFPE) samples from NSCLC patients (<i>n</i> = 174) were included in a two-phase study. Phase I: Validation of the platform by comparing the results with conventional real-time PCR and next-generation sequencing (NGS) platform. Phase II: <i>EGFR</i> mutation detection on microfluidics-based platform as part of routine diagnostics workup. The microfluidics-based platform demonstrates 96.5% and 89.2% concordance with conventional real-time PCR and NGS, respectively. The system efficiently detects mutations across the <i>EGFR</i> gene with 88.23% sensitivity and 100% specificity. Out of 144 samples analysed in phase II, the platform generated valid results in 94% with mutation detected in 41% of samples. This microfluidics-based platform can detect as low as 5% mutant allele fractions from the FFPE samples. Therefore the microfluidics-based platform is a rapid, complete walkaway, with minimum tissue requirement (two sections of 5 μ thickness) and technical skill requirement. The method can detect clinically actionable <i>EGFR</i> mutations efficiently and can be considered a reliable diagnostic platform in resource-limited settings. From receiving samples to reporting the results this platform provides accurate data without much manual intervention. The study helped to devise an algorithm that emphasizes effective screening of the NSCLC cases for <i>EGFR</i> mutations with varying tumour content. Thus it helps in triaging the cases judiciously before proceeding with multigene testing.</p>","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":"105 3","pages":"90-99"},"PeriodicalIF":3.0,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140876421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trilobatin contributes to the improvement of myopathy in a mouse model of Duchenne muscular dystrophy","authors":"Túlio de Almeida Hermes,&nbsp;Paula Fratini,&nbsp;Beatriz Godinho Nascimento,&nbsp;Laís Leite Ferreira,&nbsp;Giuliana Petri,&nbsp;Fernando Luiz Affonso Fonseca,&nbsp;Alzira Alves de Siqueira Carvalho,&nbsp;David Feder","doi":"10.1111/iep.12502","DOIUrl":"10.1111/iep.12502","url":null,"abstract":"<p>Duchenne muscular dystrophy (DMD) occurs due to genetic mutations that lead to a deficiency in dystrophin production and consequent progressive degeneration of skeletal muscle fibres, through oxidative stress and an exacerbated inflammatory process. The flavonoid trilobatin (TLB) demonstrates antioxidant and anti-inflammatory potential. Its high safety profile and effective action make it a potent therapy for the process of dystrophic muscle myonecrosis. Thus, we sought to investigate the action of TLB on damage in a DMD model, the mdx mouse. Eight-week-old male animals were treated with 160 mg/kg/day of trilobatin for 8 weeks. Control animals were treated with saline. Following treatment, muscle strength, serum creatine kinase (CK) levels, histopathology (necrotic myofibres, regenerated fibres/central nuclei, Feret's diameter and inflammatory area) and the levels of catalase and NF-κB (western blotting) of the quadriceps (QUA), diaphragm (DIA) and tibialis anterior (TA) muscles were measured. TLB was able to significantly increase muscle strength and reduce serum CK levels in dystrophic animals. The QUA of mdx mice showed a reduction in catalase and the number of fibres with a centralized nucleus after treatment with TLB. In the DIA of dystrophic animals, TLB reduced the necrotic myofibres, inflammatory area and NF-κB and increased the number of regenerated fibres and the total fibre diameter. In TA, TLB increased the number of regenerated fibres and reduced catalase levels in these animals. It is concluded that in the mdx experimental model, treatment with TLB was beneficial in the treatment of DMD.</p>","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":"105 2","pages":"75-85"},"PeriodicalIF":3.0,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140110222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TGFβR1 inhibition drives hepatocellular carcinoma proliferation through induction of toll-like-receptor signalling","authors":"Fatma El Zahraa Ammar Mohamed,&nbsp;Bedair Dewidar,&nbsp;Tao Lin,&nbsp;Matthias P. Ebert,&nbsp;Steven Dooley,&nbsp;Nadja M. Meindl-Beinker,&nbsp;Seddik Hammad","doi":"10.1111/iep.12501","DOIUrl":"10.1111/iep.12501","url":null,"abstract":"<p>Transforming growth factor (TGF)-β and toll-like receptors (TLRs) have been shown to independently modulate the proliferation of hepatocellular carcinoma (HCC). Since a direct cross-talk between these two signalling pathways in HCC has not been clearly described before, we aimed here to explore the possibility of such interaction. A human HCC tissue array (<i>n</i> = 20 vs. four control samples), human HCC samples (<i>n</i> = 10) and steatohepatitis-driven murine HCC samples (control, NASH and HCC; <i>n</i> = 6/group) were immunostained for TGFβR1, pSMAD2, TRAF6, IRAK1 and PCNA. The results were confirmed by immunoblotting. Effects of constant activation of the SMAD pathway by constitutive expression of ALK5 or knockdown of mediators of TLR signalling, IRAK1 and MyD88, on HCC proliferation, were investigated in the HCC cell line (HUH-7) after treatment with TGFβ1 cytokine or TGFβR1 kinase inhibitor (LY2157299) using PCNA and MTS assay. TGFβR1 expression is decreased in human and murine HCC and associated with downregulated pSMAD2, but increased IRAK1, TRAF6 and PCNA staining. TGFβR1 kinase inhibition abolished the cytostatic effects of TGFβ1 and led to the induction of IRAK1, pIRAK1 and elevated mRNA levels of TLR-9. Overexpression of ALK5 and knockdown of MyD88 or IRAK1 augmented the cytostatic effects of TGFβ1 on HUH-7. In another epithelial HCC cell line, that is, HepG2, TGFβR1 kinase inhibitor similarly elevated cellular proliferation. There is a balance between the canonical SMAD-driven tumour-suppressing arm and the non-canonical tumour-promoting arm of TGFβ signalling. Disruption of this balance, by inhibition of the canonical pathway, induces HCC proliferation through TLR signalling.</p>","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":"105 2","pages":"64-74"},"PeriodicalIF":3.0,"publicationDate":"2024-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139702497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}