Checkpoint inhibitors (CPIs) have been widely applied in the treatment of patients with bladder cancer (BLCA). However, there is still unmet need to dissect response predict biomarkers. To uncover CPI response-related marker genes in cancer cells, we utilized SCISSOR, integrating single-cell RNA and bulk RNA sequencing data. Transcriptomic and clinical data from IMvigor210, UNC-108, and BCAN/HCRN datasets were collected to evaluate and validate the identified biomarkers and signatures. Additionally, we analyzed TCGA-BLCA and local-BLCA RNA-seq data to investigate alternative splicing events (ASEs). Cell viability was assessed in T24 and UMUC3 cells with RBM17 upregulation or downregulation. Through SCISSOR analysis, we discovered that the expression levels of RBM17, TAP1, and PSMB8 were significantly associated with CPI response. Since PSMB8 displayed a highly positive correlation with TAP1, we developed a CPI response score (CRS) signature based on the expression profiles of RBM17 and TAP1. The CRS demonstrated robust predictive capacity in IMvigor210, UNC-108, and BCAN/HCRN datasets and was associated with higher tumor mutational burden (TMB), PD-L1 expression, and unique genomic features. Notably, RBM17 was not linked to the clinical outcomes of BLCA patients but positively correlated with BLCA cell proliferation in vitro. In the meantime, RBM17 was correlated with higher activity in core biological pathways, including antigen processing machinery, CD8 + T effector cells, cell cycle, DNA damage repair, epithelial-mesenchymal transition, histone regulation, and immune checkpoints. Moreover, the high-RBM17 group showed enrichment of LumU/Ba/sq subtypes but fewer FGFR3 alterations. Lastly, RBM17 significantly upregulated ASEs in BLCA samples, leading to higher neoantigen levels, a more inflamed tumor microenvironment, and improved CPI response. RBM17 is associated with higher ASEs and neoantigen levels, thereby potentiating the efficacy of CPI in BLCA. The established predictive signature, utilizing only two genes, has the potential to streamline clinical applications, providing a cost-effective alternative to expensive genomic, transcriptomic, and biological feature tests.

Backgrounds Ampullary adenocarcinoma (AMPAC) is a rare malignancy, treated as pancreatic or intestinal cancer based on its histologic subtype. Little is known about the genomic features of Chinese patients with AMPAC. Materials and methods We enrolled 145 Chinese AMPAC patients in our local cohort and performed a compressive somatic and germline genetic testing using a 156 gene panel. Expression of PD-L1 (clone 28 − 8) was also assessed in tumor specimens from 64 patients. Results The frequency of genetic alterations (GAs) in Chinese patients with AMPAC was found to be distinctive, with TP53 , KRAS , SMAD4 , APC , CTNNB1 , ARID1A , and CDKN2A emerged as the most frequently mutated genes. Comparing with Western patients, significant differences were observed in the prevalence of PIK3CA and ARID2 . Furthermore, the incidence of MSI-H was lower in the Chinese cohort, with only two patients identified as MSI-H. Conversely, 11 patients (8.27%) had pathogenic/likely pathogenic germline alterations, all of which were in the DNA damage response (DDR) pathway. In our cohort, 34.48% (22/64) of patients exhibited positive PD-L1 expression in tumor cells, and this expression was associated with GAs in CTNNB1 and BLM . Importantly, over three-fourths of Chinese AMPAC patients in our study had at least one actionable GA, with more than one-fifth of them having actionable GAs classified as Level 3. These actionable GAs were primarily involved in the DDR and PI3K pathways. Notably, GAs in the DDR pathway were detected in both Chinese and Western patients, and regardless of their functional impact, these alterations demonstrated enhanced overall survival rates and higher tumor mutational burden (TMB) levels. Conclusion These findings underscore the distinct genomic landscape of Chinese AMPAC patients and highlight the potential for targeted therapies based on the identified GAs.

Backgrounds Endometrial carcinoma (EC) is one of the most commonly diagnosed gynecologic malignancy in China. However, the genetic profile of Chinese EC patients has not been well established yet. Methods In current study, 158 Chinese EC patients were subjected to next-generation sequencing assay (74 took testing of EC-related 20-genes panel, and 84 took the expanded panel). Of the 158 patients, 91 patients were performed germline mutation testing using the expanded panel. Moreover, the public datasets from TCGA and MSKCC were utilized to compare the genomic differences between Chinese and Western EC patients. The proteomic and transcriptomic from CPTAC and TCGA were derived and performed unsupervised clustering to identify molecular subtypes. Results Among the 158 patients analyzed, a significant majority (85.4%) exihibited at least one somatic alteration, with the most prevalent alterations occurring in PTEN , PIK3CA , TP53 , and ARID1A . These genomic alterations were mainly enriched in the PI3K, cell cycle, RAS/RAF/MAPK, Epigenetic modifiers/Chromatin remodelers, and DNA damage repair (DDR) signaling pathways. Additionally, we identified ten individuals (11.0%) with pathogenic or likely pathogenic germline alterations in seven genes, with the DDR pathway being predominantly involved. Compared to Western EC patients, Chinese EC patients displayed different prevalence in AKT1 , MET , PMS2 , PIK3R1 , and CTCF . Notably, 69.6% of Chinese EC patients were identified with actionable alterations. In addition, we discovered novel molecular subtypes in ARID1A wild-type patients, characterized by an inferior prognosis, higher TP53 but fewer PTEN and PIK3CA alterations. Additionally, this subtype exhibited a significantly higher abundance of macrophages and activated dendritic cells. Conclusion Our study has contributed valuable insights into the unique germline and somatic genomic profiles of Chinese EC patients, enhancing our understanding of their biological characteristics and potential therapeutic avenues. Furthermore, we have highlighted the presence of molecular heterogeneity in ARID1A-wild type EC patients, shedding light on the complexity of this subgroup.

Background: Proteasome 26S subunit, ATPase gene (PSMC) family members play a critical role in regulating protein degradation and are essential for tumor development. However, little is known about the integrative function and prognostic significance of the PSMC gene family members in lung cancer.Methods: First, we assessed the expression and prognostic features of six PSMC family members in pan-cancer from The Cancer Genome Atlas (TCGA) dataset. Hence, by focusing on the relationship between PSMC genes and the prognostic, genomic, and tumor microenvironment features in lung adenocarcinoma (LUAD), a PSMC-based prognostic signature was established using consensus clustering and multiple machine learning algorithms, including the least absolute shrinkage and selection operator (LASSO) Cox regression, CoxBoost, and survival random forest analysis in TCGA and GSE72094. We then validated it in three independent cohorts from GEO and estimated the correlation between risk score and clinical features: genomic features (alterations, tumor mutation burden, and copy number variants), immune profiles (immune score, TIDE score, tumor-infiltrated immune cells, and immune checkpoints), sensitivity to chemotherapy (GDSC, GSE42127, and GSE14814), and immunotherapy (IMvigor210, GSE63557, and immunophenoscore). Twenty-one patients with LUAD were included in our local cohort, and tumor samples were submitted for evaluation of risk gene and PD-L1 expression.Results: Nearly all six PSMC genes were overexpressed in pan-cancer tumor tissues; however, in LUAD alone, they were all significantly correlated with overall survival. Notably, they all shared a positive association with increased TMB, TIDE score, expression of immune checkpoints (CD276 and PVR), and more M1 macrophages but decreased B-cell abundance. A PSMC-based prognostic signature was established based on five hub genes derived from the differential expression clusters of PSMC genes, and it was used to dichotomize LUAD patients into high- and low-risk groups according to the median risk score. The area under the curve (AUC) values for predicting survival at 1, 3, and 5 years in the training cohorts were all >.71, and the predictive accuracy was also robust and stable in the GSE72094, GSE31210, and GSE13213 datasets. The risk score was significantly correlated with advanced tumor, lymph node, and neoplasm disease stages as an independent risk factor for LUAD. Furthermore, the risk score shared a similar genomic and immune feature as PSMC genes, and high-risk tumors exhibited significant genomic and chromosomal instability, a higher TIDE score but lower immune score, and a decreased abundance of B and CD8(+) T cells. Finally, high-risk patients were suggested to be less sensitive to immunotherapy but had a higher possibility of responding to platinum-based chemotherapy. The LUAD samples from the local cohort supported the difference in the expression levels of these five hub genes between tumor and normal tissues and the correlation between the risk score and PD-L1 expression.Conclusion: Overall, our results provide deep insight into PSMC genes in LUAD, especially the prognostic effect and related immune profile that may predict therapeutic responses.

Background Cervical cancer is one of the most common gynecological cancers threatening women’s health worldwide. Double-stranded RNA-binding proteins (dsRBPs) regulate innate immunity and are therefore believed to be involved in virus-related malignancies, however, their role in cervical cancer is not well known. Methods We performed RNA-seq of tumor samples from cervical cancer patients in local cohort and also assessed the RNA-seq and clinical data derived from public datasets. By using single sample Gene Set Enrichment Analysis (ssGSEA) and univariate Cox analysis, patients were stratified into distinct dsRBP clusters. Stepwise Cox and CoxBoost were performed to construct a risk model based on optimal dsRBPs clusters-related differentially expressed genes (DEGs), and GSE44001 and CGCI-HTMCP-CC were employed as two external validation cohorts. Single cell RNA sequencing data from GSE168652 and Scissor algorithm were applied to evaluated the signature-related cell population. Results The expression of dsRBP features was found to be associated with HPV infection and carcinogenesis in CESC. However, only Adenosine deaminases acting on RNA (ADAR) and Dicer, Drosha, and Argonautes (DDR) exhibited significant correlations with the overall survival (OS) of CESC patients. Based on these findings, CESC patients were divided into three dsRBP clusters. Cluster 3 showed superior OS but lower levels of ADAR and DDR. Additionally, Cluster 3 demonstrated enhanced innate immunity, with significantly higher activity in cancer immunity cycles, immune scores, and levels of tumor-infiltrating immune cells, particularly CD8+ T cells. Furthermore, a risk model based on nine dsRBP cluster-related DEGs was established. The accuracy of survival prediction for 1 to 5 years was consistently above 0.78, and this model’s robust predictive capacity was confirmed by two external validation sets. The low-risk group exhibited significantly higher levels of immune checkpoints, such as PDCD1 and CTLA4, as well as a higher abundance of CD8+ T cells. Analysis of single-cell sequencing data revealed a significant association between the dsRBP signature and glycolysis. Importantly, low-risk patients showed improved OS and a higher response rate to immunotherapy, along with enduring clinical benefits from concurrent chemoradiotherapy. Conclusions dsRBP played a crucial role in the regulation of prognosis and tumor immunology in cervical cancer, and its prognostic signature provides a strategy for risk stratification and immunotherapy evaluation.

Backgrounds Despite the genomic landscape of urothelial carcinomas (UC) patients, especially those with UC of bladder (UCB), has been comprehensively delineated and associated with pathogenetic mechanisms and treatment preferences, the genomic characterization of upper tract UC (UTUC) has yet to be fully elucidated. Materials and methods A total of 131 Chinese UTUC (74 renal pelvis & 57 ureter) and 118 UCB patients were enrolled in the present study, and targeted next-generation sequencing (NGS) of 618 cancer-associated genes were conducted to exhibit the profile of somatic and germline alterations. The COSMIC database, including 30 mutational signatures, were utilized to evaluate the mutational spectrums. Moreover, TCGA-UCB, MSKCC-UCB, and MSKCC-UTUC datasets were retrieved for preforming genomic alterations (GAs) comparison analysis between Western and Chinese UC patients. Results In our cohort, 93.98% and 56.63% of UC patients were identified with oncogenic and actionable somatic alterations, respectively. Meanwhile, 11.24% of Chinese UC patients (of 14.50% and 7.63% of UTUC and UCB cases, respectively) were identified to harbor a total of 32 pathogenic/likely-pathogenic germline variants in 22 genes, with DNA damage repair (DDR)-associated BRCA1 (1.20%) and CHEK2 (1.20%) being the most prevalent. Chinese UTUC and UCB patients possessed distinct somatic genomic characteristics, especially with significantly different prevalence in KMT2D/C/A, GNAQ, ERCC2, RB1, and PPM1D. In addition, we also found notable differences in the prevalence of ELF3, TP53, PMS2, and FAT4 between renal pelvis and ureter carcinomas. Moreover, 22.90% and 33.90% of UTUC and UCB patients, respectively, had at least one deleterious/likely deleterious alteration in DDR related genes/pathways. Subsequently, mutational signature analysis revealed that UC patients with mutational signature 22, irrespective of UTUC or UCB, consistently had the markedly higher level of tumor mutational burden (TMB), which was proved to be positively correlated with the objective complete/partial response rate in the IMvigor210 cohort. By comparison, Chinese and Western UTUC patients also differed regrading GAs in oncogenic-related genes/pathways, especially in TP53, RTK/RAS, and PI3K pathways; besides, more alterations in WNT pathway but less TP53, RTK/RAS, HIPPO, and PI3K pathways were identified in Chinese UCB. Discussions The in-depth analysis of genomic mutational landscapes revealed distinct pathogenetic mechanisms between Chinese UTUC and UCB, and specific genomic characterizations could identify high risk population of UTUC/UCB and provided information regarding the selection of alternative therapeutic regimens.

Abstract Although CRISPR-Cas12a [clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 12a] combining pre-amplification technology has the advantage of high sensitivity in biosensing, its generality and specificity are insufficient, which greatly restrains its application range. Here, we discovered a new targeting substrate for LbaCas12a (Lachnospiraceae bacterium Cas12a), namely double-stranded DNA (dsDNA) with a sticky-end region (PAM−SE+ dsDNA). We discovered that CRISPR-Cas12a had special enzymatic properties for this substrate DNA, including the ability to recognize and cleave it without needing a protospacer adjacent motif (PAM) sequence and a high sensitivity to single-base mismatches in that substrate. Further mechanism studies revealed that guide RNA (gRNA) formed a triple-stranded flap structure with the substrate dsDNA. We also discovered the property of low-temperature activation of CRISPR-Cas12a and, by coupling with the unique DNA hybridization kinetics at low temperature, we constructed a complete workflow for low-abundance point mutation detection in real samples, which was fast, convenient and free of single-stranded DNA (ssDNA) transformation. The detection limits were 0.005–0.01% for synthesized strands and 0.01–0.05% for plasmid genomic DNA, and the mutation abundances provided by our system for 28 clinical samples were in accordance with next-generation sequencing results. We believe that our work not only reveals novel information about the target recognition mechanism of the CRISPR-Cas12a system, but also greatly broadens its application scenarios.

Backgrounds Urothelial carcinoma (UC) is the most common genitourinary malignancy in China. In this study, we surveyed the genomic features in Chinese UC patients and investigated the concordance of genetic alterations between circulating tumor DNA (ctDNA) in plasma and matched tumor tissue. Materials and methods A total of 112 UC patients were enrolled, of which 31 were upper tract UC (UTUC) and 81 were UC of bladder (UCB). Genomic alterations in 92 selected genes were analyzed by targeted next-generation sequencing. Results In the study cohort, 94.64, 86.61 and 62.50% of patients were identified as having valid somatic, oncogenic and actionable somatic alterations, respectively. The most frequently altered genes included TP53 , KMT2D , KDM6A , FAT4 , FAT1 , CREBBP and ARID1A . The higher prevalence of HRAS (22.0% vs 3.7%) and KMT2D (59.26% vs 34.57%) was identified in UTUC than in UCB. Comparisons of somatic alterations of UCB and UTUC between the study cohort and western cohorts revealed significant differences in mutant prevalence. Notably, 28.57, 17.86 and 47.32% of the cases harbored alterations in FGFRs, ERBBs and DNA damage repair genes, respectively. Furthermore, 75% of the patients carried non-benign germline variants, but only two (1.79%) were pathogenic. The overall concordance for genomic alterations in ctDNA and matched tumor tissue was 42.97% (0–100%). Notably, 47.25% of alterations detected in ctDNA were not detected in the matched tissue, and 54.14% of which were oncogenic mutations. Conclusions We found a unique genomic feature of Chinese UC patients. A reasonably good concordance of genomic features between ctDNA and tissue samples were identified.

AbstractBackgroundMolecular testing for alterations in oncogenic driver genes and targeted therapies have become standard procedures for non‐small cell lung cancer (NSCLC) patients. However, little evidence has shed light on the pattern of co‐existence of driver genes in NSCLC, and whether they may have different tumor features affecting immunotherapy is still unclarified.MethodsGenomic alterations in 14 lung cancer‐related genes were conducted in 3440 Chinese NSCLC patients using next‐generation sequencing. Meanwhile, tumor mutational burden and immunotherapy dataset from the Memorial sloan kettering cancer center (MSKCC) and lung adenocarcinoma dataset from The Cancer Genome Atlas (TCGA) were utilized for analyzing the impact of the co‐occurring alterations on patients’ survival following immunotherapy.ResultsIn this cohort, 90.17% of patients had at least one somatic alteration in the 14 genes, including 51% of co‐occurring alterations. TP53 and epidermal growth factor receptor (EGFR) were the most prevalent genes (54.74% and 53.55%, respectively), followed by KRAS, ERBB2, ALK, PIK3CA, ROS1, RET, MET, BRAF, KIT, FGFR1, PDGFRA, and NRAS. The prevalence of TP53, EGFR, and ERBB2 in our cohort were significantly higher than that from the TCGA database, whereas KRAS, BRAF, and PDGFRA were significantly lower than the latter. Furthermore, the patients who harbored multiple alterations (8.86%, 31/350) in eight driver genes survived longer and have a higher tumor mutation burden compared to the patients with a single alteration. Similar result was found between the patients with co‐occurring alteration of EGFR and other driver genes and the patients with single EGFR alteration. Meanwhile, we found a distinct immune cell infiltration feature between patients with single and multiple driver gene alterations, as well as between patients with only EGFR alteration and co‐occurring groups.ConclusionThis study identified a unique driver gene feature and found patients harboring co‐occurring alterations of EGFR and other driver genes may benefit from immunotherapy, which may provide more therapeutic selections for EGFR‐mutated NSCLC patients and merit additional investigation.

Background Urothelial carcinoma (UC) is the most common genitourinary malignancy in China. In this study, we studied the genomic features in Chinese UC patients, and investigated the concordance of genetic alterations between serum circulating tumor free DNA (ctDNA) and matched tumor tissue. Methods A total of 112 UC patients were enrolled, and 31 of which were upper tract UC (UTUC) and 81 were UC of bladder (UCB), respectively. Utilizing target next-generation sequencing, we analyzed genomic alterations of 92 selected genes. Results 94.64%, 86.61% and 62.50% of patients in our cohort were identified as having valid, oncogenic or actionable somatic alterations, respectively, and the most altered genes were TP53, KMT2D, KDM6A, FAT4, FAT1, CREBBP and ARID1A. HRAS (22.0% vs 3.7%) and KMT2D (59.26% vs 34.57%) were more altered in UTUC than in UCB in our cohort. Comparisons of somatic alterations of UCB and UTUC between our cohort and western cohorts revealed significant differences in gene prevalence. Notably, 28.57%, 17.86% and 47.32% of cases harbored alterations in FGFRs, ERBBs and DNA damage repair genes, respectively. Furthermore, 75% of patients carried non-benign germline variants, but only two (1.79%) were pathogenic. By comparison of ctDNA and matched tumor tissue, the overall concordance for genomic alterations was 42.97% (0-100%). 47.25% of alterations detected in ctDNA were not detected in the matched tissue, and 25.58% of which were oncogenic. Conclusions We found a unique genomic feature of Chinese UC patients. A good concordance of genomic features between ctDNA and tissue samples were identified.

Perfluorooctane sulfonate (PFOS), one member of polyfluoroalkyl chemicals (PFASs), persist in the environment and are found in relatively high concentrations in animal livers. PFOS has been shown to induce tumour of the liver in rats following chronic dietary administration. However, the molecular mechanisms involved in PFOS-induced hepatocellular hypertrophy are still not well characterized. In this study, male Sprague-Dawley rats were daily gavaged with PFOS (1 or 10 mg/kg body weight) for 28 days. Rat primary cultured Kupffer cells or hepatocytes were exposed to 100 mu M PFOS for 0-48 h. Our results showed that PFOS exposure caused serious hepatocellular damage and obvious inflammatory cell infiltration and increased serum tumour necrosis factor-a (TNF-alpha) and interleukin-6 (IL-6) levels. Particularly, PFOS exposure triggered Kupffer cell activation and significantly upregulated the expression of proliferating cell nuclear antigen (PCNA), c-Jun, c-MYC and Cyclin Dl (CyD1) in liver. In vitro, PFOS significantly induced production of TNF-alpha and IL-6 in Kupffer cells and increased PCNA, c-Jun, c-MYC and CyD1 expression in the primary hepatocytes co-cultured with Kupffer cells. However, Kupffer cell activation was mostly abolished by anti-INF-alpha or anti-IL6 treatment. Furthermore, blockage of TNF-alpha and IL-6 significantly inhibited hepatocyte proliferation by gadolinium chloride (GdCl3) pre-treatment in PFOS-treated mice and primary cultured Kupffer cells. On the other hand, NF-kappa B inhibitor (PDTC) and c-Jun amino-terminal kinase (JNK) inhibitor (SP600125) significantly inhibited production of PFOS-induced INF-alpha and IL-6. Taken together, these data suggest that PFOS induces Kupffer cell activation, leading to hepatocyte proliferation by through the NF-kappa B/TNF-alpha/IL-6-dependent pathway. (C) 2018 Elsevier Ltd. All rights reserved.

Exposure to particulate matter (PM) leads to kinds of cardiopulmonary diseases, such as asthma, COPD, arrhythmias, lung cancer, etc., which are related to PM-induced inflammation. We have found that PM2.5 (aerodynamics diameter <2.5 µm) exposure induces inflammatory response both in vivo and in vitro. Since the toxicity of PM is tightly associated with its size and components, PM1 (aerodynamics diameter <1.0 µm) is supposed to be more toxic than PM2.5 . However, the mechanism of PM1 -induced inflammation is not clear. Recently, emerging evidences prove that microRNAs play a vital role in regulating inflammation. Therefore, we studied the regulation of miR-146a in PM1 -induced inflammation in human lung bronchial epithelial BEAS-2B cells. The results show that PM1 induces the increase of IL-6 and IL-8 in BEAS-2B cells and up-regulates the miR-146a expression by activating NF-κB signaling pathway. Overexpressed miR-146a prevents the nuclear translocation of p65 through inhibiting the IRAK1/TRAF6 expression, and downregulates the expression of IL-6 and IL-8. Taken together, these results demonstrate that miR-146a can negatively feedback regulate PM1 -induced inflammation via NF-κB signaling pathway in BEAS-2B cells.

Perfluorooctane sulphonate (PFOS) has been reported to accumulate in liver and cause damage. The molecular mechanism of the PFOS-induced hepatotoxicity has not been completely elucidated. The aim of the present study was to investigate whether PFOS-induced oxidative stress plays an important role in liver damage, and if so, what pathway it undergoes for the mechanism of its toxicological action. Male Sprague-Dawley (SD) rats were orally administrated with PFOS at single dose of 1 or 10 mg/kg body weight for 28 consecutive days. Increased serum levels of liver enzymes and abnormal ultra structural changes were observed in the PFOS-exposed rats. Particularly, PFOS exposure significantly increased intracellular reactive oxygen species (ROS) and nitric oxide (NO) production, but weakened intracellular antioxidant defence by inhibiting catalase and superoxide dismutase activities. Signal transduction studies showed that PFOS exposure significantly elevated inducible nitric oxide synthase (iNOS), Bax, cytochrome c, cleaved caspase-9 and cleaved caspase-3, indicating the mitochondria-dependent apoptotic pathway was activated. On the other hand, significant alterations of the PFOS-induced protein expression of NF-κB and IκBα in association with an enhanced level of TNF-α were observed. Taken together, these results indicate that mitochondria play an important role in PFOS-induced hepatotoxicity.

Studies demonstrated that perfluorooctane sulfonate (PFOS) tends to accumulate in the liver and is capable to cause hepatomegaly. In the present study, we investigated the roles of miR-155 in PFOS-induced hepatotoxicity in SD rats and HepG2 cells. Male SD rats were orally administrated with PFOS at 1 or 10mg/kg/day for 28days while HepG2 cells were treated with 0–50μM of PFOS for 24h or 50μM of PFOS for 1, 3, 6, 12 or 24h, respectively. We found that PFOS significantly increased the liver weight and serum alanine transaminase (ALT) and aspartate amino transferase (AST) levels in rats. Morphologically, PFOS caused actin filament remodeling and endothelial permeability changes in the liver. Moreover, PFOS triggered reactive oxygen species (ROS) generation and induced apoptosis in both in vivo and in vitro assays. Immunoblotting data showed that NF-E2-related factor-2 (Nrf2) expression and activation and its target genes were all suppressed by PFOS in the liver and HepG2 cells. However, PFOS significantly increased miR-155 expression. Further studies showed that pretreatment of HepG2 cells with catalase significantly decreased miR-155 expression and substantially increased Nrf2 expression and activation, resulting in reduction of PFOS-induced cytotoxicity and oxidative stress. Taken together, these results indicated that miR-155 plays an important role in the PFOS-induced hepatotoxicity by disrupting Nrf2/ARE signaling pathway.

目的 研究全氟辛烷磺酸盐(PFOS)染毒SD大鼠后,其对大鼠肝脏毒性及细胞色素P450(CYP450)亚型mRNA表达的影响.方法 40只SD雄性大鼠,随机分为5组:4个PFOS染毒组,染毒剂量分别为0.5、1.0、3.0和10.0mg/(kg·d),1个对照组.连续灌胃染毒28 d后,分析血清生化指标和观察肝脏病理变化,并检测肝脏CYP450各亚型mRNA的表达水平.结果 与对照组相比,大鼠染毒PFOS 28 d后,各染毒组大鼠的体重明显降低,10.0 mg/kg染毒组大鼠的肝脏重量显著增加.各染毒组大鼠的血清谷丙转氨酶、胆汁酸等水平显著升高,三酰甘油、总胆同醇含量降低.病理检查发现,各染毒组大鼠的肝脏细胞出现浊肿、变性,甚至坏死.此外,3.0和10.0 mg/kg组大鼠肝脏的CYP1A2 mRNA水平降低,而CYP17A1 mRNA水平升高.各染毒组CYP2B1 mRNA水平均升高,呈剂量效应关系.结论 PFOS的肝毒性呈剂量效应关系,并对CYP450的各个亚型有不同影响.