Targeting TRIM40 signaling reduces esophagus cancer development: A mechanism involving in protection of oroxylin A.

Oroxylin A (OA), a naturally active O-methylated flavone derived from Scutellaria baicalensis, is regarded as a potential drug with strong anticancer effects. Unfortunately, our understanding of the antineoplastic mechanism of oral exposure to such flavonoids is inadequate. Growing evidence has confirmed the important role of OA in the regulation of oxidative stress- and inflammatory-response-induced tissue injury. However, it remains unknown whether OA is capable of mitigating esophagus cancer (EC) progression and its potential molecular mechanism. Furthermore, the tripartite motif containing 40 (TRIM40) is a ubiquitin ligase that mediates the immune response. The potential molecular function of TRIM40 in regulating EC is largely unknown. We confirmed that OA-triggered oxidative stress markedly upregulates TRIM40. During the OA challenge, increased TRIM40 reduced oxidative stress and promoted the ER stress response. Inversely, deletion of TRIM40 facilitated oxidative stress and blocked cancer cell growth in vivo and in vitro. Mechanistically, in response to OA treatment, TRIM40 directly interacts with Keap1 and promotes ubiquitin-proteasome degradation, thus leading to the promotion of Nrf2 nuclear translocation and its downstream cascade activation, which increases antioxidant defense and cell survival. TRIM40 expression was positively correlated with Nrf2 expression and negatively associated with Keap1 expression in EC xenografts and human specimens. In addition, high TRIM40 expression correlates with poor patient survival in EC. The findings suggested that oral exposure to OA significantly mitigates EC development by targeting TRIM40 activity. These findings further elucidated the potential role of TRIM40 in EC progression by mediating Keap1 degradation, which could be considered a therapeutic target for the treatment of such a disease.

Stage-Specific PET Radiomic Prediction Model for the Histological Subtype Classification of Non-Small-Cell Lung Cancer.

PURPOSE: To investigate the impact of staging on differences in glucose metabolic heterogeneity between lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) by 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) textural analysis and to develop a stage-specific PET radiomic prediction model to distinguish lung ADC from SCC. PATIENTS AND METHODS: Patients who were histologically diagnosed with lung ADC or SCC and underwent pretreatment 18F-FDG PET/CT scans were retrospectively identified. Radiomic features were extracted from a semiautomatically outlined tumor region in the Chang-Gung Image Texture Analysis (CGITA) software package. The differences in radiomic parameters between lung ADC and SCC were compared stage-by-stage in 253 consecutive NSCLC patients with stages I to III disease. The least absolute shrinkage and selection operator (LASSO) algorithm was used for feature selection. A radiomic signature for each stage was subsequently constructed and evaluated. Then, an individual nomogram incorporating the radiomic signature and clinical risk factors was established and evaluated. The performance of the constructed models was assessed by receiver operating characteristic (ROC) curve analysis, and the nomogram was further validated by calibration curve analysis. RESULTS: The performance of the radiomic signature for distinguishing lung ADC and SCC in both the training and validation cohorts was good, with AUCs of 0.883, 0.854, and 0.895 in the training cohort and 0.932, 0.944, and 0.886 in the validation cohort for stages I, II, and III NSCLC, respectively. The radiomic-clinical nomogram integrating radiomic features with independent clinical predictors exhibited more favorable discriminative performance, with AUCs of 0.982, 0.963, and 0.979 in the training cohort and 0.989, 0.984, and 0.978 in the validation cohort for stages I, II, and III, respectively. CONCLUSION: Differences in PET radiomic features between lung ADC and SCC varied in different stages. Stage-specific PET radiomic prediction models provided more favorable performance for discriminating the histological subtype of NSCLC.

Ultrasound-targeted microbubble destruction of calcium channel subunit α 1D siRNA inhibits breast cancer via G protein-coupled receptor 30.

Estrogen has been closely associated with breast cancer. Several studies reported that Ca2+ signal and Ca2+ channels act in estrogen-modulated non-genomic pathway of breast cancer, however little was revealed on the function of L-type Ca2+ channels. The L-type Ca2+ channel subunit α 1D, named Cav1.3 was found in breast cancer cells. We aimed to investigate the expression and activity of Cav1.3 in human breast cancer, and reveal the effect of estrogen in regulating the expression of Cav1.3. The qRT-PCR and western blotting were employed to show that Cav1.3 was highly expressed in breast cancer tissues. E2 exposure rapidly upregulated the expression of Cav1.3 in dosage- and time-dependent manner, and promoted Ca2+ influx. The silencing of G protein-coupled estrogen receptor 30 (GPER1/GPR30) using siRNA transfection inhibited the upregulation of Cav1.3 and Ca2+ influx induced by E2. Moreover, the inhibition of Cav1.3 by siRNA transfection suppressed E2-induced second peak of Ca2+ signal, the expression of p-ERK1/2, and the cell proliferation. Ultrasound-targeted microbubble destruction (UTMD) of Cav1.3 siRNA was used in MCF-7 cells in vitro and in the tumor xenografts mice in vivo. The application of UTMD significantly suppressed the tumor growth and promoted the survival rate. In conclusion, E2 upregulated the expression of Cav1.3 for Ca2+ influx to promote the expression of p-ERK1/2 for cell proliferation. The study confirmed that the mechanism of E2 inducing the expression of Cav1.3 through a non-genomic pathway, and highlighted that UTMD of Cav1.3 siRNA is a powerful promising technology for breast cancer gene therapy.

Evaluation of in vivo antitumor effects of low-frequency ultrasound-mediated miRNA-133a microbubble delivery in breast cancer.

MicroRNAs (miRNAs), as a novel class of small noncoding RNAs, have been identified as important transcriptional and posttranscriptional inhibitors of gene expression. Ultrasound-targeted microbubble destruction (UTMD) is a noninvasive method for microRNA delivery. We aimed to investigate the effect of UTMD of miR-133a on breast cancer treatment. It has been reported that miRNA-133a is involved in various cancers. miR-133a was lowly expressed in breast cancer tissues and breast cancer cell lines MCF-7 and MDA-MB-231. The miR-133a expression was significantly upregulated under exogenous miRNA-133a treatment in MCF-7 and MDA-MB-231 cells analyzed by qRT-PCR. Exogenous miR-133a promoted the cell proliferation as determined by diphenyl tetrazolium bromide (MTT) assay and 5-ethynyl-2'-deoxyuridine (EdU) staining. Epidermal growth factor receptor (EGFR) expression and Akt phosphorylation were significantly suppressed after miR-133a transfection by western blot detection. We prepared the miR-133a-microbubble and injected it into breast cancer xenografts. The miR-133a-microbubble injection prolonged miR-133a circulatory time by detecting the amount of miRNA-133a in the plasma. No significant toxicity was observed on alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels at liver and albumin, blood urea nitrogen, or creatine kinase levels at kidney after miR-133a-microbubble injection. The tumor size of miR-133a-microbubble-injected mice was smaller than that of the control group. Furthermore, the delivery efficiency of miR-133a with low frequency was higher than that with common frequency. miR-133a suppressed cell proliferation by suppressing the expression of EGFR and the phosphorylation of Akt. UTMD of miR-133a inhibited the tumor growth and improved the survival rate in breast cancer mice. Our study provides new evidence that UTMD of miRNA is a promising platform for breast cancer therapy.

Antitumor effects of combining tumor radiation with the antivascular action of ultrasound stimulated microbubbles.

OBJECTIVE: More and more evidence indicates tumor vasculature plays an important role in tumor radiation response. In this study, we investigated ultrasound stimulated microbubbles to enhance the effects of radiation. METHODS: Human bladder cancer HT-1376 xenografts in severe combined immuno-deficient mice were used. High-frequency (25 MHz) ultrasound was used to image tumor responses caused by ultrasound-stimulated microbubbles in combination with radiation. Human bladder xenografts grown in severe combined immunodeficiency (SCID) mice were treated using microbubbles stimulated with ultrasound at 250, 570, or 750 kPa, and exposed to 0, 2, or 8 Gy of radiation. Tumors were imaged prior to treatment and 24 hours after treatment. Spectral analysis of images acquired from treated tumors revealed overall increases in ultrasound backscatter intensity and the spectral intercept parameter. RESULTS: There existed a synergistic effect in vivo with combined single treatments of ultrasound-stimulated microbubble vascular perturbation and radiation inducing an over 10-fold greater cell kill with combined treatments. We further demonstrate that induction of ceramide-related endothelial cell apoptosis, leading to vascular disruption, is a causative mechanism. In vivo experiments with ultrasound and bubbles permit radiation doses to be decreased significantly for comparable effect. CONCLUSION: We envisage this unique combined ultrasound-based vascular perturbation and radiation treatment method being used to enhance the effects of radiation in a tumor, leading to greater tumor eradication.

The clinical analysis of acute pancreatitis in colorectal cancer patients undergoing chemotherapy after operation.

Acute pancreatitis is a rare complication in postoperative colorectal cancer patients after FOLFOX6 (oxaliplatin + calcium folinate +5-FU [5-fluorouracil]) chemotherapy. In this paper, a total of 62 patients with gastrointestinal cancer were observed after the burst of acute pancreatitis. Surgery of the 62 cases of colorectal cancer patients was completed successfully. But when they underwent FOLFOX6 chemotherapy, five patients got acute pancreatitis (8.06%), four (6.45%) had mild acute pancreatitis, and one (1.61%) had severe acute pancreatitis, of which two were males (3.23%) and three females (4.84%). No patients (0.00%) had acute pancreatitis on the 1st day after chemotherapy; one patient (1.61%) got it in the first 2 and 3 days after chemotherapy; and three others (4.83%) got it in the first 4 days after chemotherapy. In the 62 patients with malignant tumors, the body mass index (BMI) was less than 18 (underweight) in six of them, with two cases of acute pancreatitis (33.33%); the BMI was 18-25 (normal weight) in 34 cases, with one case (2.94%) of acute pancreatitis; the BMI was 25-30 (overweight) in 13 cases, with 0 cases (0.00%) of acute pancreatitis; and the BMI was ≥30 (obese) in nine patients, with two cases of acute pancreatitis (22.22%). After symptomatic treatment, four patients were cured and one died; the mortality rate was 1.61%. Most of them appeared in the first 4 days after chemotherapy; the probability of this complication is significantly higher in slim and obese patients than in normal weight patients. Postoperative colorectal cancer patients after FOLFOX6 chemotherapy have a sudden onset of acute pancreatitis occult, especially in patients with severe acute pancreatitis; the symptoms are difficult to control, there is high mortality and it is worthy of clinician's attention.