Colorectal cancer cell-secreted exosomal miRNA N-72 promotes tumor angiogenesis by targeting CLDN18.

Angiogenesis is essential for the growth and metastasis of several malignant tumors including colorectal cancer (CRC). The molecular mechanism underlying CRC angiogenesis has not been fully elucidated. Emerging evidence indicates that secreted microRNAs (miRNAs) may mediate the intercellular communication between tumor cells and neighboring endothelial cells to regulate tumor angiogenesis. In addition, exosomes have been shown to carry and deliver miRNAs to regulate angiogenesis. miRNA N-72 is a novel miRNA that plays a regulatory role in the EGF-induced migration of human amnion mesenchymal stem cells. However, the relation between miRNA N-72 and cancer remains unclear. We here found that CRC cells could secrete miRNA N-72. A high miRNA N-72 level was detected in the serum of CRC patients and the cultured CRC cells. Moreover, the CRC cell-secreted miRNA N-72 could promote the migration, tubulogenesis, and permeability of endothelial cells. In addition, the mouse xenograft model was used to verify the facilitating effects of miRNA N-72 on CRC growth, angiogenesis, and metastasis in vivo. Further mechanism analysis revealed that CRC cell-secreted miRNA N-72 could be delivered into endothelial cells via exosomes, which then inhibited cell junctions of endothelial cells by targeting CLDN18 and consequently promoted angiogenesis. Our findings reveal a novel mechanism of CRC angiogenesis and highlight the potential of secreted miRNA N-72 as a therapeutic target and a biomarker for CRC.

HDAC10 Inhibits Cervical Cancer Progression through Downregulating the HDAC10-microRNA-223-EPB41L3 Axis.

BACKGROUND: Although the tumorigenesis of cervical cancer (CC) has been widely investigated and recognized, the study of the systematic impact of histone deacetylase 10 (HDAC10), microRNA, and downstream molecular mechanisms in CC is still limited. Herein, cervical cancer, precancer lesions, and normal cervical tissues were collected to test the expression level of HDAC10, miR-223, and EPB41L3. The mechanism of HDAC10, miR-223, and EPB41L3 was interpreted in cervical cancer cells after HDAC10, miR-223, or EPB41L3 expression was altered. RESULTS: HDAC10 was poorly expressed in cervical cancer and precancer lesions, while miR-223 was highly expressed in cervical cancer. HDAC10 bound to miR-223, and miR-223 targeted EPB41L3. HDAC10 depressed the invasion property and tumorigenesis of cervical cancer via downregulating miR-223 and subsequently targeting EPB41L3. CONCLUSION: The study clarifies that HDAC10 inhibits cervical cancer by downregulating miR-223 and subsequently targeting EPB41L3 expression, which might provide a new insight for management upon cervical cancer and precancer lesions.

Cysteine-rich intestinal protein 1 enhances the progression of hepatocellular carcinoma via Ras signaling.

The present study aimed to explore the expression and clinical significance of cysteine-rich intestinal protein 1 (CRIP1) mRNA in the serum of patients with hepatocellular carcinoma (HCC). Reverse transcription polymerase chain reaction (RT-PCR) was performed to explore the level of CRIP1 mRNA in the tissues and serum of patients with HCC. Our data showed that the mRNA level of CRIP1 was significantly elevated in the serum and tissues of HCC patients. Moreover, serum CRIP1 mRNA was significantly elevated in HCC patients with larger tumor sizes and higher tumor node metastasis (TNM) stages. Receiver operating characteristic analysis showed that compared with a single marker, the combined detection of alpha-fetoprotein, carcinoembryonic antigen, and CRIP1 had the highest accuracy, sensitivity, and specificity. Further study showed that the overexpression of CRIP1 enhanced the proliferation and migration of HepG2 cells, but the inhibition of CRIP1 decreased the proliferation and migration of HepG2 cells. Microarray assays and KyotoEncyclopedia of Genes and Genomes (KEGG) pathway analysis showed that overexpression of CRIP1 induced the activation of Ras signaling. Co-immunoprecipitation (Co-IP) assays indicated that CRIP1 could interact with Ras. To further evaluate whether CRIP1 interacts with Ras, a specific siRNA targeting Ras was selected. We found that Ras knockdown reduced the activation of Ras/AKT signaling even in HepG2 cells transfected with CRIP1. Moreover, elevated expression of CRIP1 increased the proliferation of HepG2 cells, but such effects could be abolished by silencing Ras. In summary, elevated CRIP1 levels enhanced the progression of CRIP1 via Ras signaling.

Glucocorticoid attenuates acute lung injury through induction of type 2 macrophage.

BACKGROUND: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe inflammatory lung diseases. Methylprednisolone (MP) is a common drug against inflammation in clinic. In this study, we aim to investigate the protective effect of MP on ALI and potential mechanisms. METHODS: Male BABL/c mice were injected through tail vein using lipopolysaccharide (LPS, 5 mg/kg) with or without 5 mg/kg MP. Lung mechanics, tissue injury and inflammation were examined. Macrophage subsets in the lung were identified by flow cytometry. Macrophages were cultured from bone marrow of mice with or without MP. Then, we analyzed and isolated the subsets of macrophages. These isolated macrophages were then co-cultured with CD4+ T cells, and the percentage of regulatory T cells (Tregs) was examined. The expression of IL-10 and TGF-ß in the supernatant was measured. The Tregs immunosuppression function was examined by T cell proliferation assay. To disclose the mechanism of the induction of Tregs by M2c, we blocked IL-10 or/and TGF-ß using neutralizing antibody. RESULTS: Respiratory physiologic function was significantly improved by MP treatment. Tissue injury and inflammation were ameliorated in the MP-treated group. After MP treatment, the number of M1 decreased and M2 increased in the lung. In in vitro experiment, MP promoted M2 polarization rather than M1. We then induced M1, M2a and M2c from bone marrow cells. M1 induced more Th17 while M2 induced more CD4+CD25+Fxop3+ Tregs. Compared with M2a, M2c induced more Tregs, and this effect could be blocked by anti-IL-10 and anti-TGF-ß antibodies. However, M2a and M2c have no impact on Tregs immunosuppression function. CONCLUSION: In conclusion, MP ameliorated ALI by promoting M2 polarization. M2, especially M2c, induced Tregs without any influence on Tregs immunosuppression function.