Background Angiopoietin-like protein 1 (ANGPTL1) has been proved to suppress tumor metastasis in several cancers. However, its extracellular effects on the pre-metastatic niches (PMNs) are still unclear. ANGPTL1 has been identified in exosomes, while its function remains unknown. This study was designed to explore the role of exosomal ANGPTL1 on liver metastasis in colorectal cancer (CRC). Methods Exosomes were isolated by ultracentrifugation. The ANGPTL1 level was detected in exosomes derived from human CRC tissues. The effects of exosomal ANGPTL1 on CRC liver metastasis were explored by the intrasplenic injection mouse model. The liver PMN was examined by vascular permeability assays. Exosomal ANGPTL1 localization was validated by exosome labeling. The regulatory mechanisms of exosomal ANGPTL1 on Kupffer cells were determined by RNA sequencing. qRT-PCR, Western Blot, and ELISA analysis were conducted to examine gene expressions at mRNA and protein levels. Results ANGPTL1 protein level was significantly downregulated in the exosomes derived from CRC tumors compared with paired normal tissues. Besides, exosomal ANGPTL1 attenuated liver metastasis and impeded vascular leakiness in the liver PMN. Moreover, exosomal ANGPTL1 was mainly taken up by KCs and regulated the KCs secretion pattern, enormously decreasing the MMP9 expression, which finally prevented the liver vascular leakiness. In mechanism, exosomal ANGPTL1 downregulated MMP9 level in KCs by inhibiting the JAK2-STAT3 signaling pathway. Conclusions Taken together, exosomal ANGPTL1 attenuated CRC liver metastasis and impeded vascular leakiness in the liver PMN by reprogramming the Kupffer cell and decreasing the MMP9 expression. This study suggests a suppression role of exosomal ANGPTL1 on CRC liver metastasis and expands the approach of ANGPTL1 functioning.
Purpose. Colorectal cancer is one of the most common malignant primary tumors, prone to metastasis, and associated with a poor prognosis. As autophagy is closely related to the development and treatment of colorectal cancer, we investigated the potential prognostic value of long noncoding RNA (lncRNA) associated with autophagy in colorectal cancer. Methods. In this study, we acquired information on the expression of lncRNAs in colorectal cancer from the Cancer Genome Atlas (TCGA) database and found that 860 lncRNAs were associated with autophagy-related genes. Subsequently, univariate Cox regression analysis was used to investigate 32 autophagy-related lncRNAs linked to colon cancer prognosis. Subsequently, eight of the 32 autophagy-related lncRNAs (i.e., long intergenic nonprotein coding RNA 1503 [LINC01503], ZEB1 antisense RNA 1 [ZEB1-AS1], AC087481.3, AC008760.1, AC073896.3, AL138756.1, AL022323.1, and TNFRSF10A-AS1) were selected through multivariate Cox regression analysis. Based on these autophagy-related lncRNAs, a risk signature was constructed, and the patients were divided into high- and low-risk groups. Results. The high-risk group’s overall survival time was significantly shorter than that of the low-risk group p < 0.0001 . Receiver operating characteristic curve analysis was performed to further confirm the validity of the model (area under the curve: 0.689). Moreover, multivariate regression suggested that the risk score was a significant prognostic risk factor in colorectal cancer. Gene set enrichment analysis showed that these gene sets are significantly enriched in cancer-related pathways, such as Kirsten rat sarcoma viral oncogene homolog (KRAS) signaling. Conclusion. The risk signature of eight autophagy-related lncRNAs has prognostic potential for colorectal cancer. These autophagy-related lncRNAs may play a vital role in the biology of colorectal cancer.
Oestrogen receptor (ER) is expressed in approximately 60%‐70% of human breast cancer. Clinical trials and retrospective analyses have shown that ER‐positive (ER+) tumours are more tolerant to chemotherapeutic drug resistance than ER‐negative (ER−) tumours. In addition, isobavachalcone (IBC) is known as a kind of phytoestrogen with antitumour effect. However, the underlying mechanism of IBC in ER+ breast cancer needs to be elucidated further. Our in vitro experiments showed that IBC could attenuate 17β‐estradiol (E2)‐induced paclitaxel resistance and that E2 could stimulate CD44 expression in ER+ breast cancer cells but not in ER− cells. Meanwhile, E2 could promote ERα expression to render ER+ breast cancer cells resistant to paclitaxel. Furthermore, we established paclitaxel‐resistant breast cancer cell lines and determined the function of ERα in the enhancement of paclitaxel resistance via the regulation of CD44 transcription. IBC down‐regulated ERα and CD44 expression and thus inhibited tumour growth in paclitaxel‐resistant xenograft models. Overall, our data demonstrated for the first time that IBC could decrease CD44 expression level via the ERα pathway and make ER+ breast cancer cells sensitive to paclitaxel treatment.
Colorectal cancer (CRC) is highly prevalent worldwide, but there has been limited development of efficient and affordable treatment. Induced autophagy has recently been recognized as a novel therapeutic strategy in cancer treatment, and disulfiram (DSF), a well-known antialcohol drug, is also found to inhibit tumor growth in various malignancies. Recently, DSF has been reported to induce excessive autophagy in oral squamous cells; however, little is known about whether it can induce autophagy and suppress proliferation in CRC. In this study, we investigate the effect of DSF with copper (DSF/Cu) on CRC both in vitro and in vivo and find that the combination significantly inhibits CRC cell viability and mainly induces autophagy instead of apoptosis. Furthermore, we use whole genome CRISPR library screening and identify a new mechanism by which DSF triggers autophagy by ULK1. Overall, these findings provide a potential CRC treatment.
RAB family proteins participate in the dynamic regulation of cellular membrane compartments and are dysregulated in a variety of tumor types, which may alter the biological properties of cancer cells such as proliferation, migration, and invasion. In our previous study, we found that Ras-related protein Rab-31 (RAB31) expression was increased in late-stage colorectal cancer (CRC). The role of RAB31 has never been investigated in CRC. In this study, we found that expression of RAB31 in the tumor stroma but not cancer cells of colon cancer predicted poor survival. RAB31 can be detected in primary cancer-associated fibroblasts (CAFs) and paired normal fibroblasts. Conditioned medium (CM) from RAB31 overexpressing CAFs significantly promoted migration of colon cancer cell lines in vitro and in vivo. This process may be mediated by paracrine action of hepatocyte growth factor (HGF), which was increased in the CM of RAB31-overexpressing CAFs. Blockade of HGF/MET signaling by drug inhibition, knockdown of mesenchymal to epithelial transition factor (MET) in RKO, or antibody neutralization of HGF abolished migration of RKO cells mediated by RAB31 expression in CAFs. We propose that in colon cancer, increased RAB31 expression in CAFs may contribute to tumor progression by regulating the secretion of HGF in the tumor stroma.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.