Atherosclerosis is a chronic and multifactorial inflammatory disease and is closely associated with cardiovascular and cerebrovascular diseases. circRNAs can act as competing endogenous RNAs to mRNAs and function in various diseases. However, there is little known about the function of circRNAs in atherosclerosis. In this study, three rabbits in the case group were fed a high-fat diet to induce atherosclerosis and another three rabbits were fed a normal diet. To explore the biological functions of circRNAs in atherosclerosis, we analyzed the circRNA, miRNA and mRNA expression profiles using RNA-seq. Many miRNAs, mRNAs and circRNAs were identified as significantly changed in atherosclerosis. We next predicted miRNA-target interactions with the miRanda tool and constructed a differentially expressed circRNA-miRNA-mRNA triple network. A gene ontology enrichment analysis showed that genes in the network were involved in cell adhesion, cell activation and the immune response. Furthermore, we generated a dysregulated circRNA-related ceRNAs network and found seven circRNAs (ocu-cirR-novel-18038, -18298, -15993, -17934, -17879, -18036 and -14389) were related to atherosclerosis. We found these circRNAs also functioned in cell adhesion, cell activation and the immune response. These results show that the crosstalk between circRNAs and their competing mRNAs might play crucial roles in the development of atherosclerosis.

Angiotensin II (ANGII) and its receptor (AGTR1) have been proposed as significant contributors to metastasis in multiple cancers. Further, high AGTR1 levels are associated with poor epithelial ovarian cancer (EOC) outcomes. However, the mechanistic basis for these effects is unknown. Recent studies have suggested that ovarian cancer metastasis is highly dependent on the formation of multicellular spheroids (MCS). To understand the associations between the ANGII/AGTR1 pathway and cancer outcomes, we evaluated the effects of ANGII on MCS formation by ovarian cancer cells and used a proteomic approach to analyze the mechanistic basis. We used the data from the GENT database and immunohistochemistry staining to assess the AGTR1 expression in epithelial ovarian cancer (EOC) patients and to assess its role in cancer progression. Colony formation assay, 3D culture assay, and transwell assays were used to analyze the effect of ANGII on the MCS formation and cell migration. The signaling pathways of AGTR1 and transactivation of epidermal growth factor receptor (EGFR) transactivation were investigated by the western blotting analysis. Xenograft models were used to determine the role of AGTR1 in ovarian cancer metastasis. ANGII release from ovarian cancer cells and ANGII levels in the EOC ascites fluid were measured by immunoassay. A shotgun proteomic approach was used to explore the detail molecular mechanism. Modulation of lipid desaturation and endoplasmic reticulum stress were verified by the in vitro and in vivo functional assays. AGTR1 expression was negatively correlated with EOC prognosis. AGTR1activation significantly enhanced the MCS formation and cell migration. ANGII triggered both of the classical AGTR1 pathway and the EGFR transactivation. ANGII administration increased peritoneal metastasis. In addition, ovarian cancer cells secreted ANGII and enhanced cancer metastasis in a positive feedback manner. Based on the proteomic data, lipid desaturation was activated by induction of stearoyl-CoA desaturase-1 (SCD1), which suggests that inhibition of SCD1 may significantly reduce MCS formation by increasing endoplasmic reticulum stress. ANGII promotes MCS formation and peritoneal metastasis of EOC cells. AGTR1 activation increases the lipid desaturation via SCD1 upregulation, which ultimately reduces endoplasmic reticulum stress in MCS. This mechanism explained the association between high levels of AGTR1 and poor clinical outcomes in EOC patients.

Photothermal therapy (PTT) is a new treatment modality for tumors. However, the efficient delivery of photothermal agents into tumors remains difficult, especially in hypoxic tumor regions. In this study, an approach to deliver melanin, a natural photothermal agent, into tumors using genetically engineered bacteria for image‐guided photothermal and immune therapy is developed. An Escherichia coli MG1655 is transformed with a recombinant plasmid harboring a tyrosinase gene to produce melanin nanoparticles. Melanin‐producing genetically engineered bacteria (MG1655‐M) are systemically administered to 4T1 tumor‐bearing mice. The tumor‐targeting properties of MG1655‐M in the hypoxic environment integrate the properties of hypoxia targeting, photoacoustic imaging, and photothermal therapeutic agents in an “all‐in‐one” manner. This eliminates the need for post‐modification to achieve image‐guided hypoxia‐targeted cancer photothermal therapy. Tumor growth is significantly suppressed by irradiating the tumor with an 808 nm laser. Furthermore, strong antitumor immunity is triggered by PTT, thereby producing long‐term immune memory effects that effectively inhibit tumor metastasis and recurrence. This work proposes a new photothermal and immune therapy guided by an “all‐in‐one” melanin‐producing genetically engineered bacteria, which can offer broad potential applications in cancer treatment.