RESUMEN
The SOX family consists of about 20 transcription factors involved in embryonic development, reprogramming, and cell fate determination. In this study, we demonstrated that SOX4 was significantly upregulated in differentiated thyroid cancer. Immunohistochemical analysis revealed that high SOX4 expression was associated with papillary histology, extrathyroidal extension, lymph node metastasis, and advanced disease stage. Patients whose tumors exhibited high SOX4 expression had a shorter recurrence-free survival, though significance was lost in multivariate Cox regression analysis. SOX4 silencing in thyroid cancer cells slowed cell growth, attenuated clonogenicity, and suppressed anoikis resistance. Additionally, SOX4 knockdown impeded xenograft tumor growth in nude mice. Knockdown of SOX4 expression was accompanied by reduced phosphorylation of AKT and ERK. Furthermore, CRABP2 expression correlated with SOX4 expression, and SOX4 silencing decreased CRABP2 expression and its downstream effectors such as integrin ß1 and ß4. These results indicate that SOX4 has both prognostic and therapeutic implications in differentiated thyroid cancer, and targeting SOX4 may modulate tumorigenic processes in the thyroid.
RESUMEN
Among genetically engineered mouse models of breast cancer, MMTV-PyVT is a mouse strain in which the oncogenic polyoma virus middle T antigen is driven by the mouse mammary tumor virus promoter. The aim of the present study was to perform morphologic and genetic analyses of mammary tumors arising from MMTV-PyVT mice. To this end, mammary tumors were obtained at 6, 9, 12, and 16 weeks of age for histology and whole-mount analyses. We conducted whole-exome sequencing to identify constitutional and tumor-specific mutations, and genetic variants were identified using the GRCm38/mm10 mouse reference genome. Using hematoxylin and eosin analysis and whole-mount carmine alum staining, we demonstrated the progressive proliferation and invasion of mammary tumors. Frameshift insertions/deletions (indels) were noted in the Muc4. Mammary tumors showed small indels and nonsynonymous single-nucleotide variants but no somatic structural alterations or copy number variations. In summary, we validated MMTV-PyVT transgenic mice as a multistage model for mammary carcinoma development and progression. Our characterization may be used as a reference for guidance in future research.
RESUMEN
This study elucidates how high-intensity interval training (HIT) and moderate-intensity continuous training (MCT) affect mitochondrial functionality and thrombin generation (TG) in platelets following hypoxic exercise (HE, 100 W under 12% O2 for 30 min). Forty-five healthy sedentary males were randomized to engage either HIT (3-minute intervals at 40% and 80%VO2max, n = 15) or MCT (sustained 60%VO2max, n = 15) for 30 minutes/day, 5 days/week for 6 weeks, or to a control group (CTL, n = 15) that did not received exercise intervention. Before the intervention, HE (i) reduced the ATP-linked O2 consumption rate (OCR), the reserve capacity of OCR, and the activities of citrate synthase (CS) and succinate dehydrogenase (SDH), (ii) lowered mitochondrial membrane potential (MP) and elevated matrix oxidant burden (MOB) in platelets, and (iii) enhanced dynamic TG in platelet-rich plasma (PRP), which responses were attenuated by pretreating PRP with oligomycin or rotenone/antimycin A. However, 6-week HIT (i) increased mitochondrial OCR capacity with enhancing the CS and SDH activities and (ii) heightened mitochondrial MP with depressing MOB in platelets following HE, compared to those of MCT and CTL. Moreover, the HIT suppressed the HE-promoted dynamic TG in PRP. Hence, we conclude that the HIT simultaneously improves mitochondrial bioenergetics and suppresses dynamic TG in platelets undergoing hypoxia.
Asunto(s)
Plaquetas/metabolismo , Entrenamiento de Intervalos de Alta Intensidad , Mitocondrias/metabolismo , Estrés Fisiológico , Trombina/biosíntesis , Hipoxia de la Célula , Respiración de la Célula , Ciclo del Ácido Cítrico , Ejercicio Físico/fisiología , Glucólisis , Humanos , Masculino , Potencial de la Membrana Mitocondrial , Biogénesis de Organelos , Oxidantes/metabolismo , Consumo de Oxígeno , Aptitud Física , Plasma Rico en Plaquetas/metabolismo , Adulto JovenRESUMEN
This study elucidates how interval and continuous exercise regimens affect the mitochondrial functionality of lymphocytes under hypoxic stress. Sixty healthy sedentary males were randomly assigned to engage in either high-intensity interval training (HIIT, 3 min intervals at 80% and 40% VO2max, n = 20) or moderate-intensity continuous training (MICT, sustained 60% VO2max, n = 20) for 30 min/day, 5 days/week for 6 weeks or were assigned to a control group that did not receive exercise intervention (n = 20). Lymphocyte phenotypes/mitochondrial functionality under hypoxic exercise (HE, 100 W under 12% O2) were determined before and after the various interventions. Before the intervention, HE (i) increased the mobilization of senescent (CD57+/CD28-) lymphocytes into the blood, (ii) decreased the ATP-linked O2 consumption rate (OCR), the reserve capacity of OCR, and the citrate synthase activity in the mitochondria, and (iii) lowered the mitochondrial membrane potential (MP) and elevated the matrix oxidant burden (MOB) of lymphocytes. However, both HIIT and MICT significantly (i) decreased blood senescent lymphocyte counts, (ii) enhanced the mitochondrial OCR with increased citrate synthase and succinate dehydrogenase activities, (iii) increased mitochondrial MP and decreased MOB and (iv) increased the ratio of mitofusin to DRP-1 in lymphocytes after HE. Thus, we concluded that either HIIT or MICT effectively improves lymphocyte mitochondrial functionality by enhancing oxidative phosphorylation and suppressing oxidative damage under hypoxic conditions.