Activating transcription factor 6 contributes to cisplatin­induced ototoxicity via regulating the unfolded proteins response.

As a broad-spectrum anticancer drug, cisplatin is widely used in the treatment of tumors in various systems. Unfortunately, several serious side effects of cisplatin limit its clinical application, the most common of which are nephrotoxicity and ototoxicity. Studies have shown that cochlear hair cell degeneration is the main cause of cisplatin-induced hearing loss. However, the mechanism of cisplatin-induced hair cell death remains unclear. The present study aimed to explore the potential role of activating transcription factor 6 (ATF6), an endoplasmic reticulum (ER)-localized protein, on cisplatin-induced ototoxicity in vivo and in vitro. In this study, we observed that cisplatin exposure induced apoptosis of mouse auditory OC-1 cells, accompanied by a significant increase in the expression of ATF6 and C/EBP homologous protein (CHOP). In cell or cochlear culture models, treatment with an ATF6 agonist, an ER homeostasis regulator, significantly ameliorated cisplatin-induced cytotoxicity. Further, our in vivo experiments showed that subcutaneous injection of an ATF6 agonist almost completely prevented outer hair cell loss and significantly alleviated cisplatin-induced auditory brainstem response (ABR) threshold elevation in mice. Collectively, our results revealed the underlying mechanism by which activation of ATF6 significantly improved cisplatin-induced hair cell apoptosis, at least in part by inhibiting apoptosis signal-regulating kinase 1 expression, and demonstrated that pharmacological activation of ATF6-mediated unfolded protein response is a potential treatment for cisplatin-induced ototoxicity.

Copper Chaperone Atox1 Protected the Cochlea From Cisplatin by Regulating the Copper Transport Family and Cell Cycle.

Antioxidant 1 copper chaperone (Atox1) may contribute to preventing DDP cochlear damage by regulating copper transport family and cell cycle proteins. A rat model of cochlear damage was developed by placing gelatin sponges treated with DDP in the cochlea. HEI-OC1 cells were treated with 133 µM DDP as a cell model. DDP-induced ototoxicity in rats was confirmed by immunofluorescence (IF) imaging. The damage of DDP to HEI-OC1 cells was assessed by using CCK-8, TUNEL, and flow cytometry. The relationship between Atox1, a member of the copper transport protein family, and the damage to in vivo/vitro models was explored by qRT-PCR, western blot, CCK-8, TUNEL, and flow cytometry. DDP had toxic and other side effects causing cochlear damage and promoted HEI-OC1 cell apoptosis and cell cycle arrest. The over-expression of Atox1 (oe-Atox1) was accomplished by transfecting lentiviral vectors into in vitro/vivo models. We found that oe-Atox1 increased the levels of Atox1, copper transporter 1 (CTR1), and SOD3 in HEI-OC1 cells and decreased the expression levels of ATPase copper transporting α (ATP7A) and ATPase copper transporting ß (ATP7B). In addition, the transfection of oe-Atox1 decreased cell apoptosis rate and the number of G2/M stage cells. Similarly, the expression of myosin VI and phalloidin of cochlea cells in vivo decreased. Atox1 ameliorated DDP-induced damage to HEI-OC1 cells or rats' cochlea by regulating the levels of members of the copper transport family.

Activation of Nrf2 inhibits ferroptosis and protects against oxaliplatin-induced ototoxicity.

Oxaliplatin, as a third-generation platinum-based anticancer drug, is widely used in tumor therapy of many systems. Clinically, oxaliplatin has a number of serious side effects, most notably neuropathy and ototoxicity. The degeneration of cochlear hair cells is the main reason for the hearing loss caused by platinum-based drugs. However, the mechanism of oxaliplatin-induced cochlear hair cell death remains unclear. Ferroptosis is a novel cell injury pattern triggered by the accumulation of iron hydroperoxides in lipids and dependent on the participation of iron ions, which plays an important role in a variety of diseases. Whether ferroptosis is involved in oxaliplatin-induced ototoxicity has not been reported. In this study, we observed that oxaliplatin treatment resulted in lipid peroxidation and reactive oxygen species (ROS) accumulation in OC1 cells, which may be an early alteration in the occurrence of ferroptosis. Additional treatment with ferroptosis inducer or inhibitor significantly aggravated or ameliorated oxaliplatin-induced cytotoxicity. Similarly, inhibition of ferroptosis also protected cochlear hair cells against oxaliplatin-induced injury. In addition, the expression of nuclear factor erythroid 2-related factor2 (Nrf2) and heme oxygenase-1 (HO-1) was significantly increased after oxaliplatin treatment, and treatment with the Nrf2 agonist, resveratrol, dramatically attenuated cochlear hair cell damage induced by oxaliplatin. Activation of Nrf2 significantly decreased the expression of iron regulatory protein 2 (IRP-2) and reversed the expression of glutathione peroxidase 4 (GPX4). Collectively, our results demonstrated that activation of Nrf2 alleviates oxaliplatin-induced cochlear hair cell damage by inhibiting ferroptosis, which may be a new mechanism of oxaliplatin-induced ototoxicity.

The effect of nirmatrelvir-ritonavir on viral clearance and length of hospital stay in patients infected with SARS-CoV-2 omicron variants.

BACKGROUND: The pandemic of coronavirus disease 2019 (COVID-19) has caused heavy burdens on national healthcare systems. Nirmatrelvir-ritonavir (Paxlovid) may be one of the most promising therapeutic drugs, with reports of up to 89% reduction rates in hospitalization risk and death among patients with mild-to-moderate COVID-19 who are at risk of developing severe disease. However, limited studies have investigated the effects of this class of drugs on viral clearance and length of hospital stay. METHODS: In this study, we retrospectively analyzed the characteristics of patients infected with the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and investigated the effects of oral nirmatrelvir-ritonavir on viral clearance and length of hospital stay in mild-to-moderate COVID-19 patients at high risk for progression to severe disease. RESULTS: The median SARS-CoV-2 negative conversion time was 16 (13-20) versus 13 (10-16) days (control group versus nirmatrelvir-ritonavir group, p < 0.001), the median length of hospital stay was 13 (10-16) versus 12 (13-14) days (control group versus nirmatrelvir-ritonavir group, p = 0.01), and the SARS-CoV-2 negative conversion time and length of hospital stay were significantly shorter in the nirmatrelvir-ritonavir group than in the control group. When controlling for hypertension, chronic kidney disease, severity status of COVID-19, use of antibiotic agent, and COVID-19 vaccine received, multiple stepwise linear regression analysis showed that nirmatrelvir-ritonavir treatment was negatively associated with the SARS-CoV-2 negative conversion time and length of hospital stay. CONCLUSION: Nirmatrelvir-ritonavir reduces the viral clearance time and length of hospital stay in hospitalized patients with COVID-19. Nirmatrelvir-ritonavir might be a promising drug to reduce the virus load and the heavy burden of healthcare systems.

UCHL1 regulated by Sp1 ameliorates cochlear hair cell senescence and oxidative damage.

Age-related hearing loss (ARHL) is the most common cause of hearing loss in the elderly. Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme involved in several types of human disease. The present study aimed to investigate the effect of UCHL1 on a hydrogen peroxide (H2O2)-induced ARHL model in cochlear hair cells and uncover its underlying mechanism. Reverse transcription-quantitative (RT-q)PCR and western blot analysis were used to assess UCHL1 expression in HEI-OC1 cells exposed to H2O2. Following UCHL1 overexpression in H2O2-induced HEI-OC1 cells, cell activity was assessed by Cell Counting Kit-8 assay. The content of oxidative stress-associated markers including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and reactive oxygen species (ROS ) was measured using corresponding commercial kits. Cell apoptosis was evaluated by TUNEL assay and western blot analysis. Cell senescence was assessed by senescence-associated ß-galactosidase staining and western blot analysis. RT-qPCR and western blot analysis were applied to measure mRNA and protein expression levels, respectively, of specificity protein 1 (Sp1) in H2O2-treated HEI-OC1 cells. In addition, the association between UCHL1 and Sp1 was verified by luciferase reporter and chromatin immunoprecipitation (ChIP) assay. The mRNA and protein expression levels of UCHL1 were also determined in Sp1-overexpressing cells by RT-qPCR and western blot analysis, respectively. Following Sp1 overexpression in UCHL1-overexpressing H2O2-treated HEI-OC1 cells, cell activity, oxidative stress, apoptosis and senescence were assessed. Finally, the expression levels of NF-κB signaling-related proteins p-NF-κB p65 and NF-κB p65 were detected using western blot analysis. The results showed that UCHL1 was downregulated in H2O2-treated HEI-OC1 cells. In addition, UCHL1 overexpression enhanced cell viability and promoted oxidative damage, apoptosis and senescence in H2O2-induced HEI-OC1 cells. Furthermore, Sp1 was upregulated in H2O2-treated HEI-OC1 cells. Additionally, luciferase reporter and ChIP assays demonstrated that Sp1 interacted with the UCHL1 promoter to inhibit UCHL1 transcription. Sp1 overexpression reversed the effect of UCHL1 overexpression on cell viability, oxidative stress, apoptosis, senescence and activation of the NF-κB signaling pathway in H2O2-exposed HEI-OC1 cells. Collectively, the results suggested that UCHL1 transcriptional suppression by Sp1 protected cochlear hair cells from H2O2-triggered senescence and oxidative damage.

CCDC86 promotes the aggressive behavior of nasopharyngeal carcinoma by positively regulating EGFR and activating the PI3K/Akt signaling.

Nasopharyngeal carcinoma (NPC) is a common malignant tumor of the head and neck. A number of studies have confirmed that coiled-coil domain-containing protein 86 (CCDC86) plays an important role in the pathogenesis of lymphoma but the role of CCDC86 in NPC has not yet been reported. Here, in vivo and in vitro experiments were conducted to explore whether CCDC86 plays a role in the pathogenesis of NPC and to identify the specific mechanism. We found that CCDC86 was highly expressed in NPC tissues and cells, and the expression level of CCDC86 was correlated with the prognosis of patients with advanced NPC. CCDC86 promoted the proliferation, invasion, and migration of NPC cells in vivo and in vitro by promoting the EMT process and upregulating the expression of MMPs. Then, we confirmed that EGFR is a downstream target gene of CCDC86 and that CCDC86 can promote the proliferation, invasion, and migration of NPC cells by upregulating the expression of EGFR and activating downstream PI3K/Akt. Furthermore, we confirmed that CCDC86 did not directly bind to EGFR but positively regulated EGFR by binding to NPM1. CCDC86 is expected to be used as a novel biomarker and therapeutic target for predicting the prognosis of NPC.

RNA-seq analysis of the differential response to low-temperature stress in two morphs of mud crabs (Scylla paramamosain).

The mud crab (Scylla paramamosain) is an economically important crab species that is distributed along the southern coast of China. Previously we reported that various morphological types of mud crabs differentially adapt to temperature changes. This study investigates the effects of temperature on morphs with one or two spines (Sp1 and Sp2, respectively) on the outer margin of the carpus of cheliped at a low temperature (8 °C) and a control temperature (20 °C). The hepatopancreas were the transcriptome source, and a total of 81,853 unigenes were obtained by sequencing, with an average length of 420 bp, and an N50 of 1460 bp. Of these, 22.33 % were known genes. Under low-temperature stress, there were 361 differentially expressed genes (DEGs) between the two morphs; 96 and 265 were up- and down-regulated genes, respectively. There were no DEGs between the morphs at 20 °C. Functional enrichment analysis revealed that the DEGs encoded abundant metallocarboxypeptidase activity, extracellular space, proteolysis, and sequence-specific DNA binding, and were further enriched in signal pathway components, including ubiquinone and other terpenoid-quinone biosynthesis, phenylalanine metabolism, MAPK signaling pathway, apoptosis, and other signaling pathways. The gene expressions of acid phosphatase (ACP), chymotrypsin (CHY), serine carboxypeptidase (SCP), and trypsin (TRY) under low-temperature stress were detected. The expressions of ACP, CHY, and SCP gradually decreased with time. The ACP, CHY, SCP, and TRY gene expression of the Sp1 morph was lower than that of the Sp2 morph; however, the ACP gene expression of the Sp1 morph was higher than that of the Sp2 morph at several time points. In conclusion, adaptability differences between the morphs to low-temperature stress were confirmed, which will enable the selection of cold-tolerant, high-quality varieties of mud crabs for breeding.

IRF4 transcriptionally activate HOTAIRM1, which in turn regulates IRF4 expression, thereby affecting Th9 cell differentiation and involved in allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) is an inflammatory reaction caused by irritation of nasal mucosa by external allergens, which seriously affects the life of patients. Here, we aimed to investigate the effect and mechanism of long non-coding RNA HOX antisense intergenic RNA myeloid 1 (lncRNA HOTAIRM1) on AR development. METHODS: The nasal mucosa samples were collected from AR patients and AR model mice (induced by ovalbumin). T helper type 9 (Th9) cells were examined by flow cytometry. Fluorescence in situ hybridization was conducted to examine the localization of HOTAIRM1 in CD4+ T cells. Dual-luciferase reporter assay or RNA immunoprecipitation was conducted to examine the bond between HOTAIRM1 and miR-148a-3p, miR-148a-3p, and interferon regulatory factor 4 (IRF4). Chromatin Immunoprecipitation assay was conducted to detect the interaction between IRF4 and HOTAIRM1 promoter. RESULTS: HOTAIRM1, interleukin-9 (IL-9), and IRF4 were highly expressed in the AR model. The ratio of Th9 cells was increased in AR mice and overexpressing HOTAIRM1 further promoted Th9 cell differentiation, while the effect was reversed after overexpression of miR-148a-3p. Besides, in vivo experiments showed that interfering with HOTAIRM1 reduced the number of sneezing and rubbing movements, reduced immunoglobulin E (IgE) and IL-9 levels, as well as Th9 cells. HOTAIRM1 was expressed in the cytoplasm and the interactions between HOTAIRM1 and miR-148a-3p, miR-148a-3p and IRF4, were confirmed. Furthermore, IRF4 bound to the HOTAIRM1 promoter and promoted its transcriptional activation. CONCLUSION: HOTAIRM1 was highly expressed in the AR model. Besides, IRF4 activated HOTAIRM1 transcription, and HOTAIRM1, in turn, up-regulated IRF4 expression through competitively binding to miR-148a-3p with IRF4, thereby affecting Th9 cell differentiation and participating in the occurrence and development of AR. Our results suggested that interference with HOTAIRM1 might become a treatment for AR.

Circ_0067835 regulates allergic inflammatory response in type-2 innate lymphoid cells in allergic rhinitis (AR) via miR-155/GATA3.

Allergic rhinitis (AR) is a familiar respiratory allergic inflammatory disease with higher incidence. The pathogenesis of AR is particularly complex. Therefore, a lot of work is acquired to excavate deep mechanisms, thereby providing effective strategies for AR diagnose and treatment. AR mice model was induced by recombinant murine IL-33 (0.05 µg/µl) on days 1, 3, and 5. The lentiviral vectors carrying si-circ_0067835, miR-155 mimic, si-NC or miR-NC were injected into AR mice. Thus, mice were divided into control, AR, AR + si-NC, AR + si-circ_0067835, AR + si-circ_0067835 + miR-NC, and AR + si-circ_0067835 + miR-155 mimic groups. qRT-PCR experiment was used to measure the expression of circ_0067835 and miR-155. Behavioral test result was quantified to assess AR mice model. Hematoxylin and eosin (HE) staining was performed to analyze histopathological changes. Helper T cell 2 (Th2) cytokines (IL-4, IL-5, IL-9 and IL-13) and percentage of type-2 innate lymphoid cells (ILC2s) in nasal mucosa tissues in AR mice model were evaluated needing western blot, ELISA, and flow cytometry. Besides, the targeting relationship between circ_0067835 and miR-155, or between miR-155 and GATA3, was investigated via luciferase report assay. Circ_0067835 expression levels were raised in the nasal mucosa tissues of AR mice. Inhibiting circ_0067835 could reduce Type2 cytokines and ILC2s levels in AR mice model. Furthermore, circ_0067835 targeted and positively regulated miR-155 expression, and GATA3 was a downstream target of miR-155 and adjusted by circ_0067835/miR-155 axis. In addition, silencing circ_0067835 inhibited cytokines and ILC2s levels by down-regulating miR-155. Circ_0067835 effectively inhibited AR response in ILC2s through participation of miR-155/GATA3 axis.

GRß Regulates Glucocorticoid Resistance in Sudden Sensorineural Hearing Loss.

BACKGROUND: In recent years, the incidence of sudden deafness has gradually increased, with a very limited understanding of its etiology and pathogenesis. Glucocorticoids are the first choice of the treatment, but some hormone-resistant patients are not sensitive to glucocorticoid therapy. The pathogenesis is not yet known. In this study, we aim to construct the HEI-OC1 cell line stably overexpressing Glucocorticoid Receptor Beta (GRß), and identify its exact role in the cases of glucocorticoidresistant sudden deafness. METHODS: We used the endotoxin lipopolysaccharide-stimulated cochlear hair cells (HEI-OC1) to investigate the relationship of inflammation factor IL-2, TNF alpha, and SRp30c with the high expression GRß. We built a stable GRß high expression HEI-OC1 cell line and clarified its effects on the therapeutic effect of dexamethasone. MTT assay, colony formation assay, CCK-8 assay, Western blot, and RT-qPCR were utilized for characterizations. RESULTS: Dexamethasone reduced the LPS-induced inflammatory response from HEI-OC1 cells (p<0.05), detected by MTT assay. Dexamethasone could protect HEI-OC1 cells, but its protective effect was weakened due to the transfection of SRp30c over-expression plasmid (p<0.05). The transfection of SRp30c over-expression plasmid in HEI-OC1 cells could elevate the expressions of GRß (p<0.05). CONCLUSION: We clarified the mechanisms of high expression of GRß in glucocorticoid-resistant sudden sensorineural hearing loss, and proved that the inhibition of SRp30c may act as a new treatment way of glucocorticoid-resistant sudden sensorineural hearing loss.

Metformin attenuates the D­galactose­induced aging process via the UPR through the AMPK/ERK1/2 signaling pathways.

Age­related hearing loss, also termed central presbycusis, is a progressive neurodegenerative disease; it is a devastating disorder that severely affects the quality of life of elderly individuals. Substantial evidence has indicated that oxidative stress and associated protein folding dysfunction have a marked influence on neurodegenerative diseases. In this study, we aimed to cells to investigate whether metformin protects against age­related pathologies and to elucidate the underlying mechanisms; specifically, we focused on the role of unfolded protein response (UPR) via the AMPK/ERK1/2 signaling pathways. For this purpose, the biguanide compound, metformin, a medication widely used in the treatment of type 2 diabetes, was administered to rats in a model of mimetic aging. In addition, senescent PC12 were treated with metformin. Although it has been well established that UPR signaling is activated in response to cellular stress and is associated with the pathogenesis of neuronal deterioration, the detailed functions of the UPR in the auditory cortex remain unclear. We found that metformin treatment markedly affected the UPR and the AMPK/ERK1/2 signaling pathway, and maintained the auditory brainstem response (ABR) threshold during the aging process. The results indicated that the regulation of the UPR and AMPK/ERK1/2 signaling pathway by metformin significantly attenuated hearing loss, cell apoptosis and age­related neurodegeneration. Reversing these harmful effects through the use of metformin suggests its involvement in restoring the antioxidant status and protein homeostasis related to the underlying pathology of presbycusis. The findings of this study may provide a better approach for the treatment of age­related neurodegeneration diseases.

Autophagy regulates the degeneration of the auditory cortex through the AMPK-mTOR-ULK1 signaling pathway.

Presbycusis is the most common sensory impairment associated with aging; however, the underlying molecular mechanism remains unclear. Autophagy has been demonstrated to serve a key role in diverse diseases; however, no studies have examined its function in central presbycusis. The aim of the present study was to investigate the changes of autophagy in the physiological processes of the auditory cortex and its role in the degeneration of the auditory cortex, as well as the related mechanisms using naturally aging rats and a D­galactose (D­gal)­induced mimetic rat model of aging. The present study demonstrated that autophagy increased from 3 months to 15 months in the normal saline (NS) control group, while it decreased in the D­gal group. Compared with the age­matched NS group, the D­gal group demonstrated significantly increased levels of the autophagy­related proteins, LC3 and Beclin 1 (BECN1) and the anti­apoptotic proteins B­cell lymphoma (BCL)2 and BCL­extra large (BCL­xL) at 3 months, with no obvious changes in cell apoptosis level and neuron ultrastructural morphology. However, LC3, BECN1, BCL2 and BCL­xL were decreased at 15 months in the D-gal group, with cell apoptosis significantly increased and substantial neuron degeneration. Additionally, 5' AMP­activated protein kinase (AMPK) activity was enhanced, and mechanistic target of rapamycin (mTOR) and ULK1 phosphorylation (Ser 757) activities were inhibited at 3 months compared with those of the NS group, while the opposite was observed at 9 and 15 months. The present results suggested that autophagy increases from young to adult and decreases at old age in the physiological processes of the auditory cortex, and has anti­apoptotic as well as anti­aging functions in the degeneration of the auditory cortex. Additionally, autophagy was regulated through AMPK activation and mTOR suppression, and impairment of autophagy may serve a key role in the degeneration of the auditory cortex, even in the pathogenesis of central presbycusis.

Hydrogen Sulphide Treatment Increases Insulin Sensitivity and Improves Oxidant Metabolism through the CaMKKbeta-AMPK Pathway in PA-Induced IR C2C12 Cells.

Studies have reported attenuation of insulin resistance (IR) by improving phosphorylation of the insulin signalling pathway. However, the upstream molecular signalling pathway is still elusive. In this study, Western blot was used to evaluate the phosphorylation level of the insulin signalling pathway and the AMPK pathway. 2-NBDG was used to evaluate glucose uptake. Ca2+ imaging was used to assess change of intracellular Ca2+ concentration. We found that NaHS enhanced the intracellular Ca2+ concentration and glucose uptake and activated the insulin signalling cascade in a palmitic acid (PA)-induced IR model in C2C12 cells. Furthermore, activation of the IRS1/PI3K/AKT pathway and glucose uptake were decreased when AMPK or CaMKKß was inhibited. Our study also showed that the mitochondrial electron transport chain, ATP production, and intramitochondrial cAMP declined in the IR model but that this effect was reversed by NaHS, an effect that may be mediated by the Ca2+/CaMKK2/AMPK and PI3K/AKT pathways. Our data indicate that H2S improves activation of the insulin signalling cascade and glucose uptake via activation of the Ca2+/CaMKK2/AMPK pathway and mitochondrial metabolism in C2C12 cells. Furthermore, NaHS protects mitochondrial function and maintains normal ATP production by activating the cAMP system and the Ca2+/CaMKK2/AMPK and PI3K/ATK pathways.

The role of sodium hydrosulfide in attenuating the aging process via PI3K/AKT and CaMKKß/AMPK pathways.

Age-related dysfunction of the central auditory system, known as central presbycusis, is characterized by defects in speech perception and sound localization. It is important to determine the pathogenesis of central presbycusis in order to explore a feasible and effective intervention method. Recent work has provided fascinating insight into the beneficial function of H2S on oxidative stress and stress-related disease. In this study, we investigated the pathogenesis of central presbycusis and tried to explore the mechanism of H2S action on different aspects of aging by utilizing a mimetic aging rat and senescent cellular model. Our results indicate that NaHS decreased oxidative stress and apoptosis levels in an aging model via CaMKKß and PI3K/AKT signaling pathways. Moreover, we found that NaHS restored the decreased activity of antioxidants such as GSH, SOD and CAT in the aging model in vivo and in vitro by regulating CaMKKß and PI3K/AKT. Mitochondria function was preserved by NaHS, as indicated by the following: DNA POLG and OGG-1, the base excision repair enzymes in mitochondrial, were upregulated; OXPHOS activity was downregulated; mitochondrial membrane potential was restored; ATP production was increased; and mtDNA damage, indicated by the common deletion (CD), declined. These effects were also achieved by activating CaMKKß/AMPK and PI3K/AKT signaling pathways. Lastly, protein homeostasis, indicated by HSP90 alpha, was strengthened by NaHS via CaMKKß and PI3K/AKT. Our findings demonstrate that the ability to resist oxidative stress and mitochondria function are both decreased as aging developed; however, NaHS, a novel free radical scavenger and mitochondrial protective agent, precludes the process of oxidative damage by activating CaMKKß and PI3K/AKT. This study might provide a therapeutic target for aging and age-related disease.

MiR-608 rs4919510 is associated with prognosis of hepatocellular carcinoma.

Single nucleotide polymorphisms (SNPs) within microRNAs (miRNAs) are considered potential markers for risk and prognosis of various cancers. In the current study, we aimed to determine whether miR-608 rs4919510 affected hepatocellular carcinoma (HCC) prognosis. We genotyped rs4919510 using DNA from blood samples of 362 HCC patients receiving surgical resection of HCC tumor. Associations between rs4919510 and overall survival (OS) and demographic characteristics and clinical features were estimated using the Cox proportional hazards model. Results showed that HCC patients who carried the rs4919510 CC genotype had a significantly longer OS compared to those who carried the GG genotype (P = 0.013, hazard ratio [HR] = 0.600, 95 % confidence interval [CI] 0.402-0.897) and the CG + GG genotype (P = 0.033, HR = 0.681, 95 % CI 0.479-0.970) in univariate analysis. Similar results were obtained in multivariate analysis. Further stratification analysis indicated that rs4919510 was significantly associated with OS in patients who were satisfied with one of the following criteria: male gender, HbsAg-positive, α-fetoprotein (AFP)-positive, tumor size >5 cm, cirrhosis, solitary tumor, I + II pTNM stage, or no tumor capsule. Finally, a significantly higher frequency of rs4919510 CC genotype was observed in patients with cirrhosis (22.9 %, 55/240) than those without cirrhosis (14.0 %, 17/121) (P = 0.047). In conclusion, our results illustrated the potential role of miR-608 rs4919510 as a prognostic marker for HCC patients undergoing surgical resection of the tumor.

miR-492G>C polymorphism (rs2289030) is associated with overall survival of hepatocellular carcinoma patients.

Single-nucleotide polymorphisms (SNPs) of microRNAs (miRNAs) are considered potential markers of cancer risk and prognosis in various cancers. In the current study, the primary aim is to determine whether the miR-492G>C polymorphism (rs2289030) altered hepatocellular carcinoma (HCC) prognosis. The SNP rs2289030 of miR-492 was genotyped using DNA from blood samples of 362 HCC patients that had undergone surgical resection of a HCC tumor. The associations between overall survival and demographic characteristics, clinical features, and the SNP rs2289030 were estimated using the Cox proportional hazards model. Results showed that patients who carried the CG genotype (P = 0.015, hazard ratio [HR] = 0.704, 95 % confidence interval [CI] 0.530-0.934) and CG+GG genotype (P = 0.011, HR = 0.703, 95 % CI 0.536-0.924) had significantly decreased risk of death compared to those with the CC genotype. Similar results were found in the multivariate analysis adjusted by tumor size and venous invasion. Further stratification analysis indicated that the effect of rs2289030 had more prominence in patients ≤50 years old and that reported ever using alcohol, male gender, a family history of HCC, being HbsAg or alpha fetoprotein (AFP) positive, differentiation I + II, presence of venous invasion or cirrhosis, multiple tumors, and pTNM stage I + II. Results from this study illustrate the potential use of miR-492 rs2289030 as a prognostic marker for HCC patients that have undergone a surgical resection of the tumor.