Hepatocellular carcinoma (HCC) is a common malignant tumor that severely threatens human health. The poor prognosis of HCC is mainly attributed to intrahepatic and extrahepatic metastases. HOXD9 proteins belong to a superfamily that regulates the development and control of many cellular processes, including proliferation, apoptosis, cell shape, and cell migration. HOXD9 can also function as an oncogene in several cancer cells. However, its biological function in human HCC requires further investigation. In this study, HOXD9 exhibited high expression in invasive HCC cells. HOXD9 overexpression can significantly enhance HCC cell migration, invasion, and metastasis, whereas silencing HOXD9 inhibits these processes. HOXD9 also promotes the epithelial–mesenchymal transition (EMT) of HCC cells. Microarray analysis suggests that ZEB1 can function as a downstream factor of HOXD9. HOXD9 can interact with the promoter region of ZEB1 and promotes ZEB1 expression. ZEB1 knockdown inhibits HOXD9-induced migration and invasion, as well as EMT in HCC cells. This study helps elucidates the oncogenic functions of HOXD9 in HCC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0245-3) contains supplementary material, which is available to authorized users.
BackgroundRadioresistance is the major cause of cancer treatment failure. Additionally, splicing dysregulation plays critical roles in tumorigenesis. However, the involvement of alternative splicing in resistance of cancer cells to radiotherapy remains elusive. We sought to investigate the key role of the splicing factor SRSF1 in the radioresistance in lung cancer.MethodsLung cancer cell lines, xenograft mice models, and RNA-seq were employed to study the detailed mechanisms of SRSF1 in lung cancer radioresistance. Clinical tumor tissues and TCGA dataset were utilized to determine the expression levels of distinct SRSF1-regulated splicing isoforms. KM-plotter was applied to analyze the survival of cancer patients with various levels of SRSF1-regulated splicing isoforms.FindingsSplicing factors were screened to identify their roles in radioresistance, and SRSF1 was found to be involved in radioresistance in cancer cells. The level of SRSF1 is elevated in irradiation treated lung cancer cells, whereas knockdown of SRSF1 sensitizes cancer cells to irradiation. Mechanistically, SRSF1 modulates various cancer-related splicing events, particularly the splicing of PTPMT1, a PTEN-like mitochondrial phosphatase. Reduced SRSF1 favors the production of short isoforms of PTPMT1 upon irradiation, which in turn promotes phosphorylation of AMPK, thereby inducing DNA double-strand break to sensitize cancer cells to irradiation. Additionally, the level of the short isoform of PTPMT1 is decreased in cancer samples, which is correlated to cancer patients' survival.ConclusionsOur study provides mechanistic analyses of aberrant splicing in radioresistance in lung cancer cells, and establishes SRSF1 as a potential therapeutic target for sensitization of patients to radiotherapy.
The present study aimed to investigate whether klotho gene delivery attenuated renal hypertrophy and fibrosis in streptozotocin-induced diabetic rats. A recombinant adeno-associated virus (rAAV) carrying mouse klotho full-length cDNA (rAAV.mKL), was constructed for in vivo investigation of klotho expression. Diabetes was induced in rats by a single tail vein injection of 60 mg/kg streptozotocin. Subsequently, the diabetic rats received an intravenous injection of rAAV.mKL, rAAV.green fluorescent protein (GFP) or phosphate-buffered saline (PBS). The Sprague-Dawley rat group received PBS and served as the control group. After 12 weeks, all the rats were sacrificed and ELISA, immunohistochemical and histological analyses, fluorescence microscopy, semi-quantitative reverse transcription-polymerase chain reaction and western blottin were performed. A single dose of rAAV.mKL was found to prevent the progression of renal hypertrophy and fibrosis for at least 12 weeks (duration of study). Klotho expression was suppressed in the diabetic rats, but was increased by rAAV.mKL delivery. rAAV.mKL significantly suppressed diabetes-induced renal hypertrophy and histopathological changes, reduced renal collagen fiber generation and decreased kidney hypertrophy index. In addition, rAAV.mKL decreased the protein expression levels of fibronectin and vimentin, while it downregulated the mRNA expression and activity of Rho-associated coiled-coil kinase (ROCK)I in the kidneys of the diabetic rats. These results indicated that klotho gene delivery ameliorated renal hypertrophy and fibrosis in diabetic rats, possibly by suppressing the ROCK signaling pathway. This may offer a novel approach for the long-term control and renoprotection of diabetes.
With the gradual prolongation of the overall survival of cancer patients, the cardiovascular toxicity associated with oncology drug therapy and radiotherapy has attracted increasing attention. At present, the main methods to identify early cancer treatment-related cardiac dysfunction (CTRCD) include imaging examination and blood biomarkers. In this review, we will summarize the research progress of subclinical CTRCD-related blood biomarkers in detail. At present, common tumor therapies that cause CTRCD include: (1) Chemotherapy—The CTRCD induced by chemotherapy drugs represented by anthracycline showed a dose-dependent characteristic and most of the myocardial damage is irreversible. (2) Targeted therapy—Cardiovascular injury caused by molecular-targeted therapy drugs such as trastuzumab can be partially or completely alleviated via timely intervention. (3) Immunotherapy—Patients developed severe left ventricular dysfunction who received immune checkpoint inhibitors have been reported. (4) Radiotherapy—CTRCD induced by radiotherapy has been shown to be significantly associated with cardiac radiation dose and radiation volume. Numerous reports have shown that elevated troponin and B-type natriuretic peptide after cancer treatment are significantly associated with heart failure and asymptomatic left ventricular dysfunction. In recent years, a few emerging subclinical CTRCD potential biomarkers have attracted attention. C-reactive protein and ST2 have been shown to be associated with CTRCD after chemotherapy and radiation. Galectin-3, myeloperoxidas, placental growth factor, growth differentiation factor 15 and microRNAs have potential value in predicting CTRCD. In this review, we will summarize CTRCD caused by various tumor therapies from the perspective of cardio-oncology, and focus on the latest research progress of subclinical CTRCD biomarkers.
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