Pan-analysis reveals CACYBP to be a novel prognostic and predictive marker for multiple cancers.

OBJECTIVES: Cancer has emerged as a global issue in terms of public health care and treatment. The significance of calcyclin binding protein (CACYBP) in various neoplasms suggests that it may serve as a novel biomarker for numerous types of human tumors. METHODS: Our research investigated the differences in CACYBP expression between cancer tissues and normal tissues using a total of 18,787 samples from multiple centers. To explore the prognostic factor of CACYBP in cancers, we utilized Cox regression analysis and Kaplan-Meier curves. We also conducted Spearman's rank correlation analyses to determine the associations of CACYBP expression with the immune microenvironment, etc. Additionally, we applied gene set enrichment analysis to explore the underlying mechanisms of CACYBP in cancers. A partial validation of CacyBP expression in cancer tissues was performed through lung adenocarcinoma samples using Western blotting and paired t-test. RESULTS: Compared to normal tissues, CACYBP exhibited high expression levels in 14 cancer types, including breast invasive carcinoma, and low expression levels in six cancers, including glioblastoma multiforme (P < 0.05). CACYBP expression was found to be significantly associated with the prognosis of 13 cancers, including adrenocortical carcinoma (P < 0.05). CACYBP demonstrated a robust ability to distinguish 15 cancers, including cholangiocarcinoma, from their control samples (area under the curve > 0.8). Furthermore, CACYBP expression was correlated with tumor mutational burden, microsatellite instability, and immune infiltration levels, indicating its potential as an exciting target for cancer treatment. CACYBP may exert its effects on several signaling pathways, including cytokine-cytokine receptor interaction, in various cancers. Compared with paired adjacent specimens, the expression level of CacyBP protein was up-regulated in lung adenocarcinoma specimens (P < 0.05), partially validating the increased expression of CACYBP in cancers. CONCLUSIONS: CACYBP has the potential to serve as a novel prognostic and predictive marker for multiple human cancers.

Beneficial impact of cardiac heavy metal scavenger metallothionein in sepsis-provoked cardiac anomalies dependent upon regulation of endoplasmic reticulum stress and ferroptosis but not autophagy.

AIMS: Sepsis represents a profound proinflammatory response with a major contribution from oxidative injury. Here we evaluated possible impact of heavy metal scavenger metallothionein (MT) on endotoxin lipopolysaccharide (LPS)-induced oxidative stress, endoplasmic reticulum (ER) stress, autophagy, and ferroptosis enroute to myocardial injury along with interplay among these stress domains. MATERIALS AND METHODS: Echocardiographic, cardiomyocyte mechanical and intracellular Ca2+ responses were monitored in myocardia from WT and transgenic mice with cardiac-selective MT overexpression challenged with LPS. Oxidative stress, stress signaling (p38, ERK, JNK), ER stress, autophagy, and ferroptosis were scrutinized. KEY FINDINGS: RNAseq analysis revealed discrepant patterns in ferroptosis between LPS-exposed and normal murine hearts. LPS insult enlarged LV end systolic dimension, suppressed fractional shortening, ejection fraction, maximal velocity of shortening/relengthening and peak shortening, as well as elongated relengthening along with dampened intracellular Ca2+ release and reuptake. In addition, LPS triggered oxidative stress (lowered glutathione/glutathione disulfide ratio and O2- production), activation of stress cascades (p38, ERK, JNK), ER stress (GRP78, PERK, Gadd153, and IRE1α), inflammation (TNFα and iNOS), unchecked autophagy (LCB3, Beclin-1 and Atg7), ferroptosis (GPx4 and SLC7A11) and interstitial fibrosis. Although MT overexpression itself did not reveal response on cardiac function, it attenuated or mitigated LPS-evoked alterations in echocardiographic, cardiomyocyte contractile and intracellular Ca2+ characteristics, O2- production, TNFα level, ER stress and ferroptosis (without affecting autophagy, elevated AMP/ATP ratio, and iNOS). In vitro evidence revealed beneficial effects of suppression of oxidative stress, ER stress and ferroptosis against LPS-elicited myocardial anomalies. SIGNIFICANCE: These data strongly support the therapeutic promises of MT and ferroptosis in septic cardiomyopathy.

microRNA-130b-3p delivery by mesenchymal stem cells-derived exosomes confers protection on acute lung injury.

OBJECTIVE: Researchers have investigated miR-130b-3p in lung disease pathology, such as lung fibrosis. The present study was performed to elucidate the miR-130b-3p-involved mechanism in acute lung injury (ALI) through delivery by mesenchymal stem cells-derived exosomes (MSCs-Exo). METHODS: ALI mouse models were induced via intratracheal administration of lipopolysaccharide (LPS) and treated with MSCs-Exo. Lung dry-wet (W/D) ratio, inflammatory factors in the bronchoalveolar lavage fluid, pathological damage and apoptosis in the lung tissues were analyzed. Expression levels of miR-130b-3p and TGFBR1 were measured in the mouse lung tissues, and the interaction between miR-130b-3p and TGFBR1 was studied. RESULTS: MSCs-Exo relieved LPS-induced ALI in mice by reducing lung W/D ratio and inflammatory response, and attenuating lung tissue pathological damage and reducing the alveolar cell apoptosis. miR-130b-3p delivery by MSCs-Exo reduced LPS-induced ALI in mice. TGFBR1 was determined to be a downstream target gene of miR-130b-3p. Inhibition of TGFBR1 could remit LPS-induced ALI in mice. The protection mediated by MSCs-Exo carrying miR-130b-3p could be rescued by elevating TGFBR1 expression. CONCLUSION: miR-130b-3p delivery by MSCs-Exo confers protection on ALI in mice via the downregulation of TGFBR1.

TRIM2 is a novel promoter of human colorectal cancer.

OBJECTIVES: The incidence of colorectal cancer (CRC) is increasing year by year and appears to be younger, due to the low early diagnosis rate and metastasis. It is difficult to remedy by conventional treatment. Here, we reported that tripartite motif containing protein 2 (TRIM2) could promote tumor growth, invasion and metastasis of CRC via a mechanism that involved EMT both in vitro and in vivo. METHODS: First, we used immunohistochemistry to detect TRIM2 expression. Next, TCGA database was applied to the coorelation between TRIM2 and CRC progression. Then, the plasmids and lentivirus particles were used to manipulate TRIM2 expression in SW620 or HT29 cells. The assays of proliferation, adhesion, magration and invasion were employed to detect the migration and invasion ability of CRC cells. Finally, a tail injection of CRC cells was used to identify the role of TRIM2 in tumor metastasis. RESULTS: TRIM2 expression was significantly higher in CRC tissues than in non-cancerous tissues and was significantly associated with some clinicopathological factors. Forced overexpression of TRIM2 promoted CRC cell proliferation, migration and invasion in vitro, while opposing results were observed when TRIM2 was depleted by short hairpin RNA. TRIM2 expression had reversely correlated with YAP signaling, which was a novel pathway way referred to tumorigenesis. Furthermore, animal metastasis models confirmed that the in vivo results were consistent with the outcomes in vitro. TRIM2 conducts its function during CRC cell metastasis by epithelial-mesenchymal transition (EMT). These results indicate that TRIM2 is a novel promoter of human colorectal cancer.

The triggering receptor expressed by myeloid cells-1 activates TLR4-MyD88-NF-κB-dependent signaling to aggravate ventilation-induced lung inflammation and injury in mice.

The triggering receptor expressed by myeloid cells-1 (TREM-1) plays an important role in infectious and autoimmune diseases but how it contributes to ventilation-induced lung injury (VILI) and inflammation is unclear. Here, we examine the possibility that TREM-1 activates signaling dependent on Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (Myd88) and nuclear factor (NF)-κB, which leads in turn to VILI. In a mouse model of VILI, which we validated based on lung edema and histopathology as well as cytokine levels, we examine mRNA and protein levels of TREM-1, TLR4, MyD88, NF-κB and its inhibitory protein I-κB in animals subjected to ventilation at normal or high tidal volume. The extent of lung edema, injury and inflammation were higher in the high tidal volume animals, as were the expression levels of all proteins examined. Treatment with TREM-1 agonist aggravated these effects, whereas treatment with TREM-1 antagonist attenuated them. Our results suggest that aggravation of VILI by TREM-1 in mice may be associated with TLR4-MyD88-NF-κB-dependent signaling.

Role of transcriptional factor Nrf2 in the acute lung injury of mice.

OBJECTIVE: This study aimed to investigate the expression and role of Nrf2 in the acute lung injury (ALI) of mice. METHODS: A total of 60 BABL/c mice were randomly divided into 2 groups: ALI group and control group. In ALI group, ALI was introduced by injection of LPS. Immunohistochemistry was performed to detect Nrf2 expression in the lung; Western blot assay was employed to detect the expression of Nrf2 in the lung homogenate; ELISA was conducted to detect the expression of Nrf2 in the lung homogenate and BALF. RESULTS: As compared to control group, ALI mice had a high Nrf2 expression in the lung as shown in immunohistochemistry, and the Nrf2 expression in the lung homogenate and BALF also increased markedly (P<0.05). CONCLUSION: The Nrf2 expression increases in the lung and BALF of ALI mice, suggesting that Nrf2 is involved in the inflammation during ALI and may serve as a new target in the therapy of ALI.