BackgroundLiver cancer is one of the most deadly cancers in the world. There are various cells in liver tumor bulk, including liver tumor initiating cells (TICs), which account for liver tumorigenesis, drug resistance, relapse and metastasis. The homeobox (HOX) transcription factors play critical roles in many physiological and pathological processes, while, their roles in liver TICs and liver tumorigenesis remain unknown.MethodsAn unbiased screening was performed using online-available datasets. Liver TICs were sorted by FACS using surface markers CD133, CD13 and EPCAM, or enriched by oncosphere formation assay. TIC self-renewal was examined by oncosphere formation and tumor initiation assay. Loss of function and gain of function assays were performed to examine the role of lncRNA. RNA pulldown, RNA immunoprecipitation, ChIP, Western blot and double FISH were used to explore the molecular mechanism of lncRNA.ResultsHere, we examined the expression pattern of HOX transcription factors, and found HOXA10 was overexpressed in liver cancer samples. Moreover, a divergent lncRNA of HOXA10 (termed lncHOXA10 hereafter) was also highly expressed in liver cancer and liver TICs. LncHOXA10 drove liver TIC self-renewal and liver tumorigenesis through HOXA10-dependent manner. LncHOXA10 interacted with SNF2L and recruited NURF chromatin remodeling complex to HOXA10 promoter, and thus initiated the transcription of HOXA10. Through HOXA10 transcriptional regulation, lncHOXA10 activated HOXA10 in liver TICs. LncHOXA10-HOXA10 signaling can be targeted to eliminate liver TICs. Altogether, lncHOXA10 drove HOXA10 expression and thus promoted liver TIC self-renewal.ConclusionHOXA10 was the most highly expressed HOX transcription factor in liver cancer and liver TICs. LncHOXA10 drove the transcriptional activation of HOXA10. This work revealed the important role of HOX transcription factor in liver TIC self-renewal and added a new layer for liver TIC regulation.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0921-y) contains supplementary material, which is available to authorized users.
MicroRNAs play critical roles in the occurrence and progression in various cancers including colorectal cancer. Here, we found that microRNA-30a expression was significantly downregulated in colorectal cancer tissues compared to adjacent noncancerous tissues, and the suppression levels of microRNA-30a were significantly associated with tumor differentiation and lymph node metastasis. We also discovered that the expression level of microRNA-30a was inversely proportional to the invasive potential of several colorectal cancer cell lines. Moreover, overexpression of microRNA-30a in colorectal cancer cells inhibited activity of cell migration and invasion. Luciferase reporter assay confirmed metadherin could be a direct target of microRNA-30a, as the overexpression of microRNA-30a decreased metadherin expression at both the protein and messenger RNA levels. Furthermore, the knockdown of metadherin expression in SW620 significantly decreased cell metastasis and invasion. The upregulation of metadherin at the protein level negatively correlated with the expression of microRNA-30a in colorectal cancer tissues, and this upregulation could partially attenuate the effect induced by microRNA-30a. These findings indicate that microRNA-30a may act as a tumor suppressor in colorectal cancer and that microRNA-30a represses cell migration and invasion by decreasing metadherin, highlighting the therapeutic potential of microRNA-30a and metadherin in colorectal cancer treatment.
OBJECTIVE: Long non-coding RNAs (lncRNAs) are defined as transcripts longer than 200 nucleotides that are not translated into protein. Many studies have identified the association between abnormal expression of lncRNAs and specific disease states, especially in tumor-related studies. However, the precise functions of these lncRNAs are not clear. In our previous study, both lnc-GULP1-2:1 and its potential target COL3A1 were significantly downregulated in ovarian cortical tissues of POI patients compared with normal control patients. The results of GO and KEGG analysis also showed that changes in extracellular matrix-related genes play an important role in the development of POI. Therefore, we speculate that lnc-GULP1-2:1 may participate in the development of ovarian follicles by regulating the COL3A1 gene. DESIGN: Basic research study. MATERIALS AND METHODS: The lentiviral vectors were used to construct a KGN cell line with stable high expression of lnc-GULP1-2:1. Real-time PCR and western blot were used to analyze the expression of COL3A1 and lnc-GULP1-2:1. Cell proliferation was analyzed by using CCK-8 kits. RESULTS: The stable over-expression of lnc-GULP1-2:1 in KGN cells could significantly inhibit granulosa cell proliferation. Treatment of KGN cells with chemotherapeutic agents (cisplatin and paclitaxel) dose-dependently inhibited granulosa cell proliferation and promoted the expression of lnc-GULP1-2:1, whereas the cytokine TGFa, which promoted granulosa cell proliferation, inhibited the expression of lnc-GULP1-2:1. These results suggest that lnc-GULP1-2:1 may be involved in proliferation regulation of granulosa cells. Further studies found that the protein levels of COL3A1 were significantly increased in KGN cells with stable over-expression of lnc-GULP1-2:1, indicating that lnc-GULP1-2:1 regulates the expression of COL3A1. Levels of lnc-GULP1-2:1 can be down-regulated by siRNAs (5 nM, 10 nM , and 20 nM) in different concentrations of COL3A1 in KGN cells, and silencing COL3A1 could also significantly inhibit KGN cell proliferation. CONCLUSIONS: The results of this study suggest that the involvement of lnc-GULP1-2:1 in the regulation of KGN granulosa cells may partly be mediated through the regulation of its target gene COL3A1. The regulation effect of lnc-GULP1-2:1 on granulosa cell proliferation was consistent with the occurrence of POI in clinical chemotherapeutic agents, suggesting that lnc-GULP1-2:1 may be involved in the regulation of granulosa cell function in POI patients. This is the first study to discover the regulation of lnc-GULP1-2:1 in ovarian granulosa cells, which is of great significance for the further investigation of lncRNA regulation in ovarian follicle development.
Rationale: Neonatal alloimmune thrombocytopenia (NAIT) caused by anti HPA-3a antibody is rare, and the clinical features of the syndrome are not specific. Patient concerns: A male infant was noted to be irritable and physical examination revealed the presence of petechiae and bruising on the right arm and thigh after born. Diagnoses: Platelet antibodies were investigated using the monoclonal antibody-specific immobilization of platelet antigens (MAIPA) assay, platelet genotyping (HPA 1–17) was performed by polymerase chain reaction technique with sequence-specific primers (PCR-SSP). The HPA genotype of the newborn was HPA-3a/b, while that of his mother and his father were HPA-3b/b and HPA-3a/a, respectively. The sera of newborn contained antibody against the platelet of newborn's father. The HPA antibody of the newborn was identified as anti HPA-3a. The newborn was confirmed as a patient of NAIT caused by anti HPA-3a antibody. Interventions: A single dose of intravenous immunoglobulin (IVIG) 1 g/kg was administered from day 3 to day 7. Outcomes: At follow-up 3 months after discharge from the hospital, the baby was developing normally and had a normal platelet count (361 × 109/L). Lessons: NAIT caused by anti HPA-3a antibody is rare, and we believe this study can provide insights for diagnosing prospective cases. Prognosis of NAIT caused by HPA3a seems to be favorable if diagnosed and treated in a timely manner.
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