Human Cell最新文献

Angiosarcomas (AS) is a rare soft tissue sarcomas with poor treatment options and a dismal prognosis. The abnormal DNA methylation pattern has been determined as the certain clinical relevance with different angiosarcoma subtypes. However, the profound mechanism is not clear. In present study, we studied thirty-six AS with or without chronic lymphedema, and reported that DNA damage was an important factor causing DNA methylation abnormality. Furthermore, we determined that the impaired Fanconi anemia (FA) pathway contributed to severe DNA damage in AS with chronic lymphedema. We also observed that the activated FANCD2 could facilitate DNMT1 recruitment on genomic DNA. Our study uncovers a novel regulatory mechanism of FA pathway on DNA methylation, and is a benefit to advanced understanding the pathogenesis of AS, as well as providing the potential therapeutic targets for AS treatment.

This study intended to clarify the mechanism of long noncoding RNA ZBTB40-IT1 in directing human bone marrow-derived mesenchymal stromal cell (hBMSC) differentiation. hBMSCs underwent osteogenic and adipogenic induction, and an osteoporosis mouse model was established via ovariectomy (OVX). Gain- and loss-of-function approaches were utilized in hBMSCs and mice to investigate the function of ZBTB40-IT1, microRNA (miR)-514a-3p, and forkhead box O4 (FOXO4). Dual-luciferase reporter and RNA pulldown assays were applied to evaluate the binding of miR-514a-3p to ZBTB40-IT1 or FOXO4. The femur of the OVX mice had upregulated ZBTB40-IT1 and FOXO4 expression and downregulated miR-514a-3p expression. The bone mass was increased in OVX mice through ZBTB40-IT1 or FOXO4 knockdown. ZBTB40-IT1 and FOXO4 were downregulated, whereas miR-514a-3p was upregulated in osteogenesis-induced hBMSCs, which was the opposite in adipogenesis-induced hBMSCs. ZBTB40-IT1 or FOXO4 knockdown or miR-514a-3p overexpression increased ARS/ALP absorbance and RUNX2 and OCN levels but decreased fat density and PPARγ and FABP4 levels in hBMSCs. Mechanistically, ZBTB40-IT1 elevated FOXO4 expression by binding to miR-514a-3p. miR-514a-3p inhibition annulled the effects of ZBTB40-IT1 downregulation on hBMSC osteogenesis and adipogenesis, and FOXO4 overexpression abolished the impacts of miR-514a-3p upregulation on hBMSC osteogenesis and adipogenesis. Conclusively, ZBTB40-IT1 inhibition promotes the osteogenic differentiation of hBMSCs via the miR-514a-3p/FOXO4 axis, thereby increasing bone mass.

Increasing evidence has shown that long non-coding RNAs (lncRNAs), which are non-coding endogenous single-stranded RNAs, play an essential role in various physiological and pathological processes through transcriptional interference, post-transcriptional regulation, and epigenetic modification. Moreover, lncRNAs, as oncogenes or tumor suppressor genes, play an important role in the occurrence and development of human cancers. Prostate androgen-regulated transcript 1 (PART1) was initially identified as a carcinogenic lncRNA in prostate adenomas. The upregulated expression of PART1 plays a tumor-promoting role in liver, prostate, lung cancers, and other tumors. In contrast, the expression of PART1 is downregulated in esophageal squamous cell carcinoma, glioma, and other tumors, which may inhibit the tumor. PART1 plays a dual role in cancer and regulates cell proliferation, apoptosis, invasion, and metastasis through a variety of potential mechanisms. These findings suggest that PART1 is a promising tumor biomarker and therapeutic target. This article reviews the biological functions, related mechanisms, and potential clinical significance of PART1 in a variety of human cancers.

The aim of this study was to investigate the biological function and molecular mechanism of ARPC1A (actin related protein 2/3 complex subunit 1A) in prostate cancer progression. RT-qPCR and IHC results showed that the level of ARPC1A in prostate cancer tissues was significantly higher than that in adjacent tissues. The results of TCGA (the cancer genome atlas) database analysis showed that high expression of ARPC1A indicates poor prognosis in prostate cancer patients. In vitro functional experiments confirmed that downregulation of ARPC1A expression resulted in decreased cell viability and invasive ability of prostate cancer cells, as ARPC1A knockdown promoted ferroptosis. The transcriptional regulation mechanism of STAT3 (signal transduction and activators of transcription 3) on ARPC1A was elucidated by Co-IP, ChIP and luciferase reporter assays. In vivo experiments also supported the in vitro results. We propose that reduced ARPC1A expression inhibits prostate cancer cell viability and invasion in a ferroptotic manner. The ARPC1A level may serve as an independent predictor of prognosis in prostate cancer patients.

Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. The aim of the present study was to explore the expression level of tumor protein 73 (TP73) in highly malignant CRC tumors and how the long non-coding RNA tumor protein 73 antisense RNA 1 (TP73-AS1) influences that transcription. We found that TP73-AS1 was highly expressed in malignant CRC samples in The Cancer Genome Atlas (TCGA) database. We also demonstrated TP73-AS1 was expressed in thirty samples of CRC tissues collected from China Medical University patients as well as in HCT116, RKO and SW480 CRC cell lines but not in HCoEpiC or CCD-18Co normal colon cells. Only wild-type TP73-AS1, but not any of its alternate splicing isoforms, was positively correlated with tumor malignancy. TP73-AS1 transcripts were shown to be located in cell nuclei especially in close proximity to the TP73 promoter in CRC cells, but not in normal colon cells. In addition, an interaction between lysine demethylase 5A (KDM5A) and TP73-AS1 in CRC cells, but not normal colon cells, and KDM5A localization on the TP73 promoter were influenced by TP73-AS1. Interestingly, the H3K4me3 level on the TP73 promoter was reduced, but was elevated by TP73-AS1 knockdown in CRC cells. In conclusion, these results suggest a novel epigenetic role of TP73-AS1 on histone demethylation that influences TP73 transcription, and shed light on malignancy in CRC.

Cancer stem cells (CSCs) are involved in cancer recurrence and metastasis owing to their self-renewal properties and drug-resistance capacity. Lipocalin-2 (Lcn2) of the lipocalin superfamily is highly expressed in pancreatic cancer. Nevertheless, reports on the involvement of Lcn2 in the regulation of pancreatic CSC properties are scant. This study is purposed to investigate whether Lcn2 plays a crucial role in CSC renewal and stemness maintenance in pancreatic carcinoma. Immunohistochemistry results of tumor tissue chips together with Gene Expression Omnibus sequencing files confirmed that Lcn2 is highly expressed in pancreatic carcinoma compared with that in normal tissues. The exogenous expression of Lcn2 attenuated CSC-associated SOX2, CD44, and EpCAM expression and suppressed sarcosphere formation and tumorigenesis in the pancreatic carcinoma cell line PANC-1, which showed low expression of Lcn2. However, Lcn2 knockout in BxPC-3 cell line, which presented high Lcn2 expression, promoted CSC stemness, further enhancing sarcosphere formation and tumorigenesis. Moreover, Lcn2 was found to regulate stemness in pancreatic cancer depending on the activation of AKT and c-Jun. Lcn2 suppresses stemness properties in pancreatic carcinoma by activating the AKT-c-Jun pathway, and thus, it may be a novel candidate to suppress the stemness of pancreatic cancer. This study provides a new insight into disease progression.

Studies have indicated that RIG-I may act as a tumor suppressor and participate in the tumorigenesis of some malignant diseases. However, RIG-I induces distinct cellular responses via different downstream signaling pathways depending on the cell type. To investigate the biological function and underlying molecular mechanism of RIG-I in the tumorigenesis of melanoma, we constructed RIG-I knockout, RIG-I-overexpressing B16-F10 and RIG-I knockdown A375 melanoma cell lines, and analyzed the RIG-I-mediated change in the biological behavior of tumor cells in spontaneous and poly (I:C)-induced RIG-I activation. Cell proliferation, cell cycling, apoptosis and migration were detected by CCK-8 assay, BrdU incorporation assay, Annexin V-PI staining assay and Transwell assay, respectively. In vivo tumorigenicity was evaluated by tumor xenograft growth in nude mice and subsequently by Ki67 staining and TUNEL assays. Furthermore, Western blotting was utilized to explore the underlying mechanism of RIG-I in melanoma cells. Our data showed that RIG-I promotes apoptosis and inhibits proliferation by G1 phase cell cycle arrest in the melanoma cell lines. Mechanistically, RIG-I induced the phosphorylation of p38 MAPK and MAPK kinases MKK3 and MKK4. In conclusion, the current study demonstrated that RIG-I suppressed the development of melanoma by regulating the activity of the MKK/p38 MAPK signaling pathway, which is relevant to research on novel therapeutic targets for this malignant disease.

It has been reported that microRNA-203a-3p (miR-203a-3p) modulates cell proliferation, migration and invasion in a variety of cancer cell types. However, little is known about its role in lung cancer progression. The present study found that miR-203a-3p was downregulated in non-small cell lung cancer (NSCLC) cell lines and tissues. Overexpression of miR-203a-3p inhibits NSCLC cell proliferation, migration and invasion, and promotes cellular apoptosis in vitro. Restoration of miR-203a-3p expression in A549 and NCI-H520 cells enhances their chemosensitivity. Further experiments showed that DNA methyltransferase 3B (DNMT3B) was a direct target of miR-203a-3p. In addition, the present results revealed that promoter hypermethylation was the potential mechanism responsible for low miR-203a-3p expression in NSCLC. Notably, feedback regulation between miR-203a-3p and DNMT3B was observed in NSCLC. Moreover, Overexpression of miR-203a-3p reduces tumor growth in vivo. In summary, the present study has identified an miR-203a-3p-DNMT3B feedback loop that facilitates NSCLC progression.