Causal effect of porphyria biomarkers on alcohol-related hepatocellular carcinoma through Mendelian Randomization.

PURPOSE: According to some cohort studies, an association exists between acute intermittent porphyria (AIP) and liver cancer. However, establishing a definitive causal relationship between porphyria and hepatocellular carcinoma (HCC) remains challenging. Prexisting studies regarding porphyria biomarkers and alcohol-related hepatocellular carcinoma (AR-HCC) make possible an entry point. In this study, we aimed to investigate the causal relationships between biomarkers of two types of porphyria, AIP and congenital erythropoietic porphyria (CEP), and AR-HCC. METHODS: Single-nucleotide polymorphisms (SNPs) associated with porphobilinogen deaminase (PBGD) and uroporphyrinogen-III synthase (UROS), along with outcome data on AR-HCC, were extracted from public genome-wide association studies (GWAS). The GWAS data were then used to explore the potential causal relationships via a two-sample Mendelian randomization (MR) analysis. The effect estimates were calculated using the random-effect inverse-variance-weighted (IVW) method. Additionally, the Cochrane's Q test, MR-Egger test, and leave-one-out analysis were conducted to detect heterogeneity and pleiotropy in the MR results. RESULTS: Using the IVW method as the primary causal effects model in the MR analyses, we found that both PBGD (effect estimate = 1.51; 95% CI, from 1.08 to 2.11, p = 0.016) and UROS (effect estimate = 1.53; 95% CI, from 1.08 to 2.18, p = 0.018) have a significant causal effect on AR-HCC. CONCLUSION: Our findings revealed a causal effect of both PBGD and UROS on AR-HCC, suggesting that both AIP and CEP have a causal association with AR-HCC.

PRDM16 from hepatic stellate cells-derived extracellular vesicles promotes hepatocellular carcinoma progression.

Hepatocellular carcinoma (HCC) represents a lethal cancer, and most HCC cases occur in the fibrotic or cirrhotic livers. Hepatic stellate cells (HSCs), the main effector cells of liver fibrosis, could secret biological contents to maintain liver inflammation. Herein, we aimed to identify the key transcription factor secreted by extracellular vesicles (EVs) derived from HSCs and explored its oncogenic mechanism. The activated HSC cell line LX-2 was co-cultured with HCC cells with or without the EVs release inhibitor GW4869. The effects of co-culture with HSC on HCC cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition were analyzed. Co-culture with activated LX-2 enhanced HCC cell growth and motility, while GW4869 inhibited the pro-carcinogenic effect of HSC, suggesting that HSC promoted HCC progression through the secretion of EVs. HSC-derived EVs carried the key oncogenic transcription factor PRDM16, and uptake of EVs-derived PRDM16 by HCC cells activated the NOTCH1-mediated Notch signaling pathway. Knocking down PRDM16 in EVs or blocking Notch signaling in HCC cells significantly inhibited the tumor-promoting effects of HSC-derived EVs. Our study demonstrates that HSC-derived EVs activate the NOTCH1-mediated Notch signaling pathway in HCC cells by carrying PRDM16, leading to HCC progression.

COL15A1 interacts with P4HB to regulate the growth and malignancy of HepG2.2.15 cells.

Liver cancer is the fourth most common cause of cancer related deaths, ranking sixth in terms of incidence rate, and hepatocellular carcinoma (HCC) is the main type of liver cancer. Hepatitis B virus (HBV) infection is the main cause of HCC, and currently, HBV related HCC has become an important public health issue. COL15A1 encodes the alpha chain of collagen XV, a member of the FACIT collagen family, which has anti-angiogenic and anti-tumoral properties and play a vital role in tissue homeostasis in the liver, and its specific function in HBV-related HCC still needs further exploration. This study aimed to determine the regulatory role of COL15A1 in HBV-related HCC and explored the underlying mechanisms at the cellular level. Firstly, the biochip analysis results showed that the expression of COL15A1 was increased in human HBV-related HCC tissues. Furthermore, HBV induction also could significantly increase the expression of COL15A1 in hepatoma cell lines. Functionally, it found that COL15A1 silencing could significantly inhibit apoptosis and promote proliferation, migration, invasion and growth of HepG2.2.15. Mechanically, it found that COL15A1 could interact with P4HB，and its silencing could significantly increase the expression level of P4HB, thereby inhibiting the GRP76 expression and promoting growth and malignancy of HepG2.2.15 cells, revealing COL15A1 might play an anticancer role in HBV-related HCC.

Relationship between eczema and indoor environmental factors among preschool children in Haikou / 中国学校卫生

Objective@#To investigate the influencing factors of home environment on eczema in preschool children, so as to provide theoretical basis for taking effective regional prevention for preschool children.@*Methods@#From December 2020 to January 2021, a cross sectional survey of 3 049 preschool children was randomly carried out by stratified cluster sampling in Haikou kindergartens, and the impact of indoor environmental factors on preschool children s eczema was analyzed. Chi squared test and binary Logistic regressive were used to analyze the related factors.@*Results@#The prevalence of eczema in preschool children was 13.6%. Multivariate Logistic regression showed that the positive correlation factors of eczema included the new decoration in the mother s residence one year before pregnancy ( OR=1.71, 95%CI =1.09-2.68), the addition of new furniture in the child s residence when the child was 0-1 years old ( OR=1.53, 95%CI =1.03-2.27), cockroaches in the house ( OR=1.35, 95%CI =1.02-1.81) and cleaning of less than once per week ( OR=1.30, 95%CI =1.01-1.66). The starting age of children s collective life since 3 years old ( OR=0.76, 95%CI =0.60-0.96) had a negative correlation with eczema ( P <0.05).@*Conclusion@#There are multiple indoor environmental factors related to eczema among preschool children in Haikou city. Parents should take measures to prevent eczema in preschool children by paying attention to home environment and the starting age of children s collective life.

Prognostic value of SPARC in hepatocellular carcinoma: A systematic review and meta-analysis.

OBJECTIVE: Hepatocellular carcinoma (HCC) is characterized by a high degree of malignancy, rapid proliferation of tumor cells, and early liver metastasis. Resistance to multiple drugs independent of the high expression of secreted protein acidic and rich in cysteine (SPARC) is associated with a high risk of recurrence and mortality. However, the prognostic value of SPARC in patients with HCC remains unclear. Therefore, we performed a meta-analysis to evaluate the relationship between the expression of SPARC and the prognosis of patients with HCC. METHODS: We searched for relevant articles in the CNKI, PubMed, EMBASE, and Web of Science databases. The 95% confidence intervals (CIs) were calculated for combined overall survival (OS) and disease-free survival (DFS) to assess the prognostic value of expression of SPARC in patients with HCC. RESULTS: In six of the studies, SPARC expression status was significantly associated with OS (combined hazard ratio [HR], 1.38; 95% CI, 1.0-1.82; Z = 2.27, P = 0.02) but not with DFS (combined HR, 0.79; 95% CI, 0.16-4.00, Z = 0.28, P = 0.78). Therefore, it cannot be assumed that upregulated SPARC expression has an effect on DFS in patients with HCC. CONCLUSION: Elevated SPARC expression is associated with a low survival rate but not with DFS in patients with HCC. Further studies are needed to confirm our conclusions. REGISTRATION: INPLASY registration number: INPLASY202180115. https://inplasy.com/inplasy-2021-8-0115/.

MIRLET7BHG promotes hepatocellular carcinoma progression by activating hepatic stellate cells through exosomal SMO to trigger Hedgehog pathway.

Hepatocellular carcinoma (HCC), commonly caused by liver fibrosis, is a global challenge with high morbidity. Activation of hepatic stellate cells (HSCs) contributes to hepatic fibrosis. Exosomes are small vesicles that play a significant role in cell-to-cell communication. Smoothened (SMO) is the key signal transducer for Hedgehog pathway. This study was designed to study the function and underlying mechanism of SMO in HSC activation. Functional assays including 5-Ethynyl-2´-deoxyuridine, colony formation, wound healing, transwell, and sphere formation assays disclosed the function of SMO. Western blot analysis of exosome biomarkers, immunofluorescence staining assay, electron microscope, and flow cytometry revealed the existence of exosomes. Bioinformatics analyses and mechanistic assays uncovered the interplays between RNAs. Nude mice xenograft model was established to evaluate HCC tumor growth. We uncovered that SMO was an oncogene in HCC cells and was low-expressed in quiescent HSCs. Then, SMO was upregulated in HSCs cultured with HCC cells-conditioned medium. Next, it was revealed that HCC cells-derived exosomes activated HSCs by transmitting SMO to HSCs. Subsequently, we recognized that microRNA let-7b host gene (MIRLET7BHG) served as the competing endogenous RNA against miR-330-5p to upregulate SMO. In turn, SMO induced hedgehog pathway to promote GLI family zinc finger 1 (Gli1), leading to transcriptional activation of MIRLET7BHG in activated HSCs. In summary, this study demonstrated that Gli1-induced MIRLET7BHG facilitated HCC by activating HSCs through exosomal SMO to stimulate hedgehog pathway, providing a new road for HCC treatment.

Effects of miR-22 on viability, migration, invasion and apoptosis in retinoblastoma Y79 cells by targeting high-mobility group box 1.

AIM: To explore the effect of miR-22 on viability, migration, invasion and apoptosis in retinoblastoma (RB) Y79 cells and to further detect the potential mechanism. METHODS: Plasmids were constructed to change the expression level of miR-22 in Y79 cells. Real-time reverse transcription polymerase chain reaction (RT-PCR) was conducted to test the expression level of miR-22. After changing the expression of miR-22, the mRNA and protein levels of high-mobility group box 1 (HMGB1) were investigated using RT-PCR and Western blotting. The effect of miR-22 on viability was analyzed by using cell counting kit-8 (CCK-8) assay and the effect on apoptosis was detected by the flow cytometry. Wound healing migration assay and Transwell invasion assay were used to detect the effects of miR-22 on cell motility. RESULTS: miR-22 inhibited viability, migration and invasion, while promoting apoptosis, in RB Y79 cells. The inhibition rate of miR-22 overexpression group at 12, 24, 48h was 11.71%±2.54%, 21.36%±1.39% and 29.44%±1.15%, respectively. Cellular apoptosis was higher in miR-22 overexpression group (17.00%±0.39%) compared with negative control (4.38%±0.38%). miR-22 negatively mediated the expression of HMGB1. Furthermore, decreased HMGB1 significantly attenuated viability, migration and invasion, while promoting apoptosis. Enforced expression of HMGB1 partially rescued the effects of miR-22 overexpression on cell viability, migration, invasion and apoptosis. Moreover, the phosphorylated protein kinase B (p-AKT) was significantly downregulated in the HMGB1 shRNA group and miR-22 overexpression group and elevated in the HMGB1 overexpression group compared with the normal control. CONCLUSION: miR-22 inhibites viability, migration and invasion and increases apoptosis in Y79 cells by targeting HMGB1. These findings may provide a therapeutic strategy for RB.

Insulin-like growth factor 1 inhibits autophagy of human colorectal carcinoma drug-resistant cells via the protein kinase B/mammalian target of rapamycin signaling pathway.

Insulin-like growth factor 1 (IGF-1) is reported to inhibit autophagy of human colorectal carcinoma cells (HCT); however, little is known regarding the mechanisms underlying the inhibitory effect of IGF-1 on autophagy in HCT resistant strains. The present study aimed to analyze the inhibitory effect of IGF-1 on the autophagy of HCT resistant strains and its potential underlying mechanisms. The viability and apoptosis of HCT-8 colon cancer cells were analyzed, and expression levels of relevant genes and proteins were investigated using reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. Treatment of cells with IGF-1 induced apoptosis. IGF-1 treatment activated protein kinase B (AKT), which may inhibit autophagy via the AKT/mammalian target of rapamycin signaling pathway. Following inhibition of autophagy, drug resistant cells became sensitive to apoptosis induced by 5-fluorouracil.