Exosomes derived from cancer-associated fibroblasts promote tumorigenesis, metastasis and chemoresistance of colorectal cancer by upregulating circ_0067557 to target Lin28.

BACKGROUND: Cancer associated fibroblasts (CAFs) can remodel tumor microenvironment by secreting exosomes. This study aimed to investigate the role of exosomes derived from cancer-associated fibroblasts in colorectal cancer (CRC) progression. METHODS: Circular RNA (circRNA) array was used to identify differentially expressed circRNAs in exosomes from normal fibroblasts (NFs) and CAFs, and confirmed one differentially expressed circRNA circ_0067557 by real-time PCR. The effect of circ_0067557 on proliferation, metastasis, chemoresistance and apoptosis was verified by wound heal, tranwell, CCK8, sphere-forming and flow cytometry assay. RESULTS: Circ_0067557 expression in exosomes from CAFs was higher than those from NFs. CAF-derived exosomes promoted the proliferation, migration, invasion and chemoresistance of CRC cells while suppressed apoptosis. Silencing of circ_0067557 inhibited malignant phenotypes of CRC cells by targeting Lin28A and Lin28B. Moreover, CAF-derived exosomes enhanced the growth of CRC xenograft tumors. CONCLUSION: Circ_0067557/Lin28A and Lin28B signal axis may be a potential therapy target for CRC.

Unraveling temporal and spatial biomarkers of epithelial-mesenchymal transition in colorectal cancer: insights into the crucial role of immunosuppressive cells.

The occurrence and progression of tumors can be established through a complex interplay among tumor cells undergoing epithelial-mesenchymal transition (EMT), invasive factors and immune cells. In this study, we employed single-cell RNA sequencing (scRNA-seq) and spatially resolved transcriptomics (ST) to evaluate the pseudotime trajectory and spatial interactive relationship between EMT-invasive malignant tumors and immune cells in primary colorectal cancer (CRC) tissues at different stages (stage I/II and stage III with tumor deposit). Our research characterized the spatiotemporal relationship among different invasive tumor programs by constructing pseudotime endpoint-EMT-invasion tumor programs (EMTPs) located at the edge of ST, utilizing evolution trajectory analysis integrated with EMT-invasion genes. Strikingly, the invasive and expansive process of tumors undergoes remarkable spatial reprogramming of regulatory and immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), regulatory T cells (Treg), and exhausted T cells (Tex). These EMTP-adjacent cell are linked to EMT-related invasion genes, especially the C-X-C motif ligand 1 (CXCL1) and CXCL8 genes that are important for CRC prognosis. Interestingly, the EMTPs in stage I mainly produce an inflammatory margin invasive niche, while the EMTPs in stage III tissues likely produce a hypoxic pre-invasive niche. Our data demonstrate the crucial role of regulatory and immunosuppressive cells in tumor formation and progression of CRC. This study provides a framework to delineate the spatiotemporal invasive niche in CRC samples.

Idol Depletion Protects against Spontaneous Atherosclerosis in a Hamster Model of Familial Hypercholesterolemia.

Inducible degrader of low-density lipoprotein (LDL) receptor (Idol) is an E3 ubiquitin ligase coded by Idol, the target gene of liver X receptor (LXR), which primarily mediates the ubiquitination and lysosomal degradation of low-density lipoprotein receptor (LDLR). Previous studies from independent groups have shown that plasma cholesterol regulation by the LXR-Idol-LDLR axis is tissue- and species-specific, indicating that the precise molecular mechanism by which Idol modulates lipid metabolism has not been completely understood and needs to be further validated in other species. Hamster, a small rodent animal model expressing endogenous cholesterol ester transfer protein (CETP), possesses many metabolic characteristics that are different from mouse but similar to human. In this study, an Idol knockout (Idol-/-) hamster model was developed using CRISPR/Cas9 gene editing system to investigate the effect of Idol depletion on plasma lipid metabolism and atherosclerosis. Our results showed that there were no significant differences in hepatic LDLR protein and plasma cholesterol levels in Idol-/- hamsters compared with wild-type (WT) controls, which was consistent with the observation that LXR agonist treatment increased the expression of Idol mRNA in the small intestine but not in the liver of WT hamsters. However, we found that plasma triglyceride (TG) levels were significantly reduced in Idol-/- hamsters due to an enhancement of TG clearance. In addition, the morphological data demonstrated that inactivation of Idol significantly lowered plasma total cholesterol and TG levels and protected against spontaneous atherosclerotic lesions in aged LDLR knockout hamsters on a chow diet but had no effect on diet-induced atherosclerosis in hamsters lacking one copy of the Ldlr gene. In conclusion, our findings suggest that Idol can regulate plasma lipid metabolism and atherosclerosis independent of LDLR function.

Determining the effects of Ephrin Type B Receptor 6 and Type A Receptor 3 on facilitating colorectal epithelial cell malignant transformation.

Ephrin Type-A Receptor 3 (EphA3) and Ephrin Type-B Receptor 6 (EphB6) belong to the ephrin receptor group consisting of the largest subset of receptor tyrosine kinases (RTKs) and are essential for neurogenesis and embryogenesis. The current study aimed to evaluate their functional roles in transforming colorectal epithelial cells and dissect the underlying molecular mechanisms. We observed altered EphA3 and EphB6 expression in tumor tissues as compared to normal tissues in a tissue microarray study. Enforced EphB6 expression promoted IMCE cell proliferation, migration, and invasion in vitro and tumor formation in nude mice, with a stronger oncogenic activity than EphA3. Pathway analysis of differentially expressed genes from a gene microarray study provided important insight into potential mechanisms through which EphB6 may regulate the malignant transformation of colorectal epithelial cells. This study represents the first demonstration of EphB6 in enhancing colorectal epithelial cell transformation, suggesting its stipulative role in the early stage of colorectal tumorigenesis. Our findings primarily uncover novel biomarkers and therapeutic targets of colorectal cancer.