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Background Hepatocellular carcinoma (HCC), a common type of cancer, has a strong metastatic ability and poor prognosis. The tumor microenvironment is the “soil” for the occurrence and development of tumors, with exosomes playing an important role in these processes. In traditional Chinese medicine(TCM), the tumor microenvironment corresponds to the internal environment of the syndrome known as spleen deficiency (SD). Numerous studies have shown that exosomes contain high levels of miRNAs, which have been shown to contribute to tumor immune regulation and metastasis. The aim of this study was to explore the mechanisms underlying the changes in the tumor microenvironment under the condition of spleen deficiency in order to find better treatments for cancer. Methods The effects of exosomal miR-29a-3p on lung metastasis from hepatocellular carcinoma (HCC) were evaluated using the scratch test, migration test, mouse SD model, HCC model, and tail-vein injection model of lung metastasis. The western blot assay, ELISA, flow cytometry, luciferase reporter gene analysis, qRT-PCR and immunofluorescence staining were among the methods used to study the molecular mechanism of lung metastasis promotion under the SD internal environment. Results Compared with the mice with HCC only, the mice with HCC and SD symptoms secreted more miR-29a- 3p-enriched exosomes, and their tumor tissue expressed significantly higher levels of α1-integrin and lower levels of FAM167A. These changed the immune microenvironment of mice (Decreased infiltration of T cells (CD3+CD4+ and CD3+CD8+), activated α1-integrin-NF-κB signaling pathway, and secreted more interleukin inflammatory factors(IL-1β, IL-6, and IL-8), which promoted the invasion and infiltration of HCC and its lung metastasis both in vivo and in vitro. In a series of patients with liver cancer, SD was found to have affected their overall survival and relapse-free survival. Conclusion Our study showed that under conditions of SD, the body releases more miRNA-containing exosomes, changes the immune microenvironment of the body, and ultimately promotes tumor metastasis and growth. These results highlight potential therapeutic targets and methods for the prevention of cancer metastasis, which may help to screen possible anticachexia TCMs and elucidate its mechanism in the future.

Background: Dietary fat absorption involves the re-esterification of digested triacylglycerol in the enterocytes, it is a biological process catalyzed by monoacylglycerol O-acyltransferase 2 (MOGAT2, aka MGAT2), which is highly expressed in the small intestine. A previous study showed that the loss of the Mogat2 gene can prevent high-fat diet-induced obesity in mice. Obesity is associated with an increased risk of several types of cancer including postmenopausal breast cancer.Methods: We collected 147 patients with triple negative breast adenocarcinoma to explore the relationship between the expression of MOGAT2 and patient overall survival. And we generated a Mogat2-deficient mouse mammary tumor model by crossing Mogat2-deficient mice with MMTV-PyMT mice to examine the effect of losing MOGAT2 in vivo.Results: Our founding suggest that obesity was induced by a relatively high-fat diet (37% of calories from fat) in the mice with or without Mogat2 knockout. Mammary tumor development was deteriorated by a relatively high-fat diet regardless of Mogat2 deficiency. As a compensation mechanism, upregulation of diacylglycerol O-acyltransferases 1 and 2 (Dgat1 and Dgat2) in the Mogat2 deficient mice was found. Conclusions: Elevated expression of MOGAT2 in triple negative breast adenocarcinoma predicts poorer patient overall survival. With the compensation of Dgat1 and Dgat2, Mogat2 deficiency alone cannot prevent fat diet-induced obesity, nor prevent mammary tumor development in a mouse model.

Purpose: Ultra-high dose rate FLASH irradiation has been shown to cause less normal tissue damage compared with conventional irradiation, also termed “FLASH effect”. However, the underlying mechanism was scarcely known. The purpose of the present study was to determine whether FLASH and conventional irradiation would induce differential inflammatory cytokines expression. Materials and methods: Female FvB mice were randomly assigned to three different groups: non-irradiated control, conventional (CONV) and FLASH groups. Mice were irradiated at 6 to 19 Gy of CONV (0.1 Gy/s) or FLASH (38.5-600 Gy/s) irradiation using an Elekta Synergy linac (6 MeV). Mice were immobilized in prone position in a custom-designed applicator with dosimetry films positioned under the body. Dose were verified by Gafchromic films. Enzyme linked immunosorbent assay (ELISA) were performed in serum samples of the mice at 6, 18 and 31 days after irradiation for four inflammatory cytokines: tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-6 (IL-6) and IL-10. Flow cytometry using antibodies for CD3, CD8, CD4 and CD45 in blood were performed pre- and 1-week post irradiation. Results: At D6 (18-19 Gy), both IL-6 and TNF-α were elevated, and IL-10 was reduced in FLASH and CONV group, while IFN-γ was only significantly increased in conventional group, compared with control group. At D18 (10 Gy) and D31 (13-19 Gy), conventional RT significantly elevated levels of IL-6, IFN-γ and TNF-α and reduced IL-10 level compared with FLASH group and control group. Additionally, even low dose conventional irradiation (13 Gy) could induce higher level of pro-inflammatory cytokines and lower level of anti-inflammatory cytokine than high dose (17-19 Gy) FLASH irradiation at D31. Flow cytometry showed that the CD8+/CD45+ ratio in the blood were higher in the conventional than in FLASH. These data indicate that minor inflammatory cytokine levels of serum in FLASH could be result of the absent of immune overactivation induced by conventional irradiation. Conclusions: Ultra-high dose rate electron FLASH caused less inflammatory cytokine levels of serum which might be a result from less CD8+/CD45+ ratio in the blood. Thus, differential cytokines and CD8+ T cell expression between FLASH and conventional irradiation would be a potential mechanism for “FLASH effect”.

BackgroundAccumulating evidence has shown that dysregulated expression of microRNAs plays a key role in tumorigenesis. To explore the mechanisms of this we conducted this study.MethodsFive Gene Expression Omnibus datasets (GEO) datasets , GSE32960, GSE36682, GSE43039, GSE70970 and GSE118613 and head and neck squamous cell carcinoma data of The Cancer Genome Atlas (TCGA) were analysis in this study.ResultsBy analyzing the microRNA expression profile of nasopharyngeal carcinoma (NPC) in the five GEO datasets, we identified miR-150-5p as potential biomarker for patient survival. To explore the mechanisms of this, We examined the head and neck squamous cell carcinoma data of TCGA and found that miR-150-5p was correlated with high enrichment of tumor-infiltrating B cells, low enrichment of cancer-associated fibroblasts and down-regulated oncogenic pathways. miR-150-5p may also improve the immune response in the tumor microenvironment. These findings may explain how miR-150-5p improves outcome of head and neck squamous cell carcinoma patients including NPC. Additionally, the exosomal long non-coding RNA AC073130.1 was identified as a potential regulator of miR-150-5p. As miR-150-5p can also be released via exosomes, this study provides insight into the cross-talk of tumor cells and B cells in the tumor microenvironment via exosomal AC073130.1 and miR-150-5p. ConclusionMiR-150-5p improves outcome of head and neck squamous cell carcinoma patients by improving the immune response. There might be a cross-talk of tumor cells and B cells in the tumor microenvironment via exosomal AC073130.1 and miR-150-5p.

Background: Dietary fat absorption involves the re esterification of digested triacylglycerol in the enterocytes, it is a biological process catalyzed by monoacylglycerol O acyltransferase 2 (MOGAT2, aka MGAT2), which is highly expressed in the small intestine. A previous study showed that the loss of the Mogat2 gene can prevent high fat diet induced obesity in mice. Obesity is associated with an increased risk of several types of cancer including postmenopausal breast cancer.Methods: We collected 147 patients with triple negative breast adenocarcinoma to explore the relationship between the expression of MOGAT2 and patient overall survival. And we generated a Mogat2 deficient mouse mammary tumor model by crossing Mogat2 deficient mice with MMTV PyMT mice to examine the effect of losing MOGAT2 in vivo. Results: Our founding suggest that obesity was induced by a relatively high fat diet (37% of calories from fat) in the mice with or without Mogat2 knockout. Mammary tumor development was deteriorated by a relatively high fat diet regardless of Mogat2 deficiency. As a compensation mechanism, upregulation of diacylglycerol O acyltransferases 1 and 2 (Dgat1 and Dgat2) in the Mogat2 deficient mice was found. Conclusions: Elevated expression of MOGAT2 in triple negative breast adenocarcinoma predicts poorer patient overall survival. With the compensation of Dgat1 and Dgat2, Mogat2 deficiency alone cannot prevent fat diet induced obesity, nor prevent mammary tumor development in a mouse model.

Background: The extracellular matrix (ECM) component serglycin promotes the epithelial-to-mesenchymal transition (EMT) and metastasis in an autocrine manner. However, the detailed mechanism underlying the roles of serglycin in Hepatocellular carcinoma (HCC) metastasis progression remains to be clarified.Methods: Analyzing 123 patients’ serum by ELISA to investigate the association between serglycin expression and HCC metastasis and prognosis. Serglycin, CRISPLD2, and YAP were overexpressed or knocked down with vector or RNAi. The RNA - sequence was used to screen serglycin downstream effectors, followed by bioinformatics, ChIP-PCR, luciferase, and promoter site mutation to identify novel target genes. The metastatic abilities of serglycin were demonstrated by a series of in vitro and in vivo experiments. Immunofluorescence, flow cytometry, and western blotting were carried out to demonstrate the potential mechanisms of serglycin.Results: We observed that serglycin was overexpressed in HCC tissues and serum, and its level was associated with metastasis and poor prognosis. By gain- and loss-of-function approaches, we found serglycin affects migratory motility and metastatic capacity in vitro and in vivo, and it's significantly associated with the stemness-like properties. Interestingly, serglycin activated the effector YAP of Hippo pathway, and further study verified the crucial role of serglycin/YAP in tumorigenesis by the DEN-induced HCC mouse model. Furthermore, the CRISPLD2 was selectively upregulated by serglycin, the axis of serglycin / YAP / CRISPLD2 regulated metastatic capacity in HCC cells, it revealed CRISPLD2 was the direct target gene of serglycin-mediated YAP/TEAD1 complex. Besides, serglycin-mediated YAP pathway enhanced cell sorafenib resistance, sorafenib combined with verteporfin reversed serglycin-mediated cellular insensitivity to sorafenib therapy.Conclusions: Autocrine ECM serglycin plays a crucial role in the process of stemness maintenance, tumorigenesis, and metastasis via selective reactivation of the novel YAP/CRISPLD2 developmental axis promotes metastasis and sorafenib resistance in Hepatocellular carcinoma, YAP-TEAD1 inhibitor verteporfin reversed serglycin-mediated cellular sorafenib resistance.