Exosomal microRNA-92b Is a Diagnostic Biomarker in Breast Cancer and Targets Survival-Related MTSS1L to Promote Tumorigenesis.

Exosomal microRNAs (miRNAs) are novel, non-invasive biomarkers for facilitating communication and diagnosing cancer. However, only a few studies have investigated their function and role in the clinical diagnosis of breast cancer. To address this gap, we established a stable cell line, MDA-MB-231-CD63-RFP, and recruited 112 female participants for serum collection. We screened 88 exosomal miRNAs identified through microarray analysis of 231-CD63 and literature screening using real-time PCR; only exosomal miR-92b-5p was significantly increased in patients with breast cancer. It had a significant correlation with stage and discriminated patients from the control with an AUC of 0.787. Exosomal miR-92b-5p impacted the migration, adhesion, and spreading ability of normal human mammary epithelial recipient cells through the downregulation of the actin dynamics regulator MTSS1L. In clinical breast cancer tissue, the expression of MTSS1L was significantly inversely correlated with tissue miR-92b-5p, and high expression of MTSS1L was associated with better 10-year overall survival rates in patients undergoing hormone therapy. In summary, our studies demonstrated that exosomal miR-92b-5p might function as a non-invasive body fluid biomarker for breast cancer detection and provide a novel therapeutic strategy in the axis of miR-92b-5p to MTSS1L for controlling metastasis and improving patient survival.

Correlation of Beta2-Glycoprotein I With Tumor Prognosis in Breast Cancer Patients.

BACKGROUND/AIM: Beta2-glycoprotein I (ß2-GPI) is a plasma glycoprotein, which has been implicated in a variety of physiological functions. However, the connection between ß2-GPI and breast cancer is mostly unknown. Breast cancer is a malignant tumor that severely impairs women's health worldwide. The aim of the study was to investigate the role of ß2-GPI in tumor cells of breast cancer patients and its correlation with tumor prognosis. MATERIALS AND METHODS: A total of 125 female patients diagnosed with breast cancer were enrolled in the study. The expression of ß2-GPI in resected breast tissues was determined by immunohistochemistry (IHC) and correlated with clinicopathological variables by the Chi-squared test. The prognostic value of ß2-GPI for overall survival (OS) and disease-free survival (DFS) was determined by Kaplan-Meier estimates and the significance of differences was evaluated by the log-rank test. RESULTS: ß2-GPI staining was predominantly observed in tumor cells of breast cancer patients and significantly correlated with tumor stage and lymph node metastasis of breast cancer. High ß2-GPI expression was significantly correlated with better OS and DFS. Moreover, DFS was found to be significantly better in patients with higher ß2-GPI expression, especially those in the early tumor stage groups. CONCLUSION: High ß2-GPI expression levels in tumor cells of breast cancer patients were independent factors predicting a better OS and DFS. ß2-GPI activation in high-risk patients may be a potential strategy for reducing breast cancer progression.

Comprehensive Transcriptomic and Proteomic Analyses Identify a Candidate Gene Set in Cross-Resistance for Endocrine Therapy in Breast Cancer.

Endocrine therapy (ET) of selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (AIs) has been used as the gold standard treatment for hormone-receptor-positive (HR+) breast cancer. Despite its clinical benefits, approximately 30% of patients develop ET resistance, which remains a major clinical challenge in patients with HR+ breast cancer. The mechanisms of ET resistance mainly focus on mutations in the ER and related pathways; however, other targets still exist from ligand-independent ER reactivation. Moreover, mutations in the ER that confer resistance to SERMs or AIs seldom appear in SERDs. To date, little research has been conducted to identify a critical target that appears in both SERMs/SERDs and AIs. In this study, we conducted comprehensive transcriptomic and proteomic analyses from two cohorts of The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) to identify the critical targets for both SERMs/SERDs and AIs of ET resistance. From a treatment response cohort with treatment response for the initial ET regimen and an endocrine therapy cohort with survival outcomes, we identified candidate gene sets that appeared in both SERMs/SERDs and AIs of ET resistance. The candidate gene sets successfully differentiated progress/resistant groups (PD) from complete response groups (CR) and were significantly correlated with survival outcomes in both cohorts. In summary, this study provides valuable clinical implications for the critical roles played by candidate gene sets in the diagnosis, mechanism, and therapeutic strategy for both SERMs/SERDs and AIs of ET resistance for the future.

MOAI: a multi-outcome interaction identification approach reveals an interaction between vaspin and carcinoembryonic antigen on colorectal cancer prognosis.

Identifying and characterizing the interaction between risk factors for multiple outcomes (multi-outcome interaction) has been one of the greatest challenges faced by complex multifactorial diseases. However, the existing approaches have several limitations in identifying the multi-outcome interaction. To address this issue, we proposed a multi-outcome interaction identification approach called MOAI. MOAI was motivated by the limitations of estimating the interaction simultaneously occurring in multi-outcomes and by the success of Pareto set filter operator for identifying multi-outcome interaction. MOAI permits the identification for the interaction of multiple outcomes and is applicable in population-based study designs. Our experimental results exhibited that the existing approaches are not effectively used to identify the multi-outcome interaction, whereas MOAI obviously exhibited superior performance in identifying multi-outcome interaction. We applied MOAI to identify the interaction between risk factors for colorectal cancer (CRC) in both metastases and mortality prognostic outcomes. An interaction between vaspin and carcinoembryonic antigen (CEA) was found, and the interaction indicated that patients with CRC characterized by higher vaspin (≥30%) and CEA (≥5) levels could simultaneously increase both metastases and mortality risk. The immunostaining evidence revealed that determined multi-outcome interaction could effectively identify the difference between non-metastases/survived and metastases/deceased patients, which offers multi-prognostic outcome risk estimation for CRC. To our knowledge, this is the first report of a multi-outcome interaction associated with a complex multifactorial disease. MOAI is freely available at https://sites.google.com/view/moaitool/home.

Comprehensive profiles and diagnostic value of menopausal-specific gut microbiota in premenopausal breast cancer.

In Western countries, breast cancer tends to occur in older postmenopausal women. However, in Asian countries, the proportion of younger premenopausal breast cancer patients is increasing. Increasing evidence suggests that the gut microbiota plays a critical role in breast cancer. However, studies on the gut microbiota in the context of breast cancer have mainly focused on postmenopausal breast cancer. Little is known about the gut microbiota in the context of premenopausal breast cancer. This study aimed to comprehensively explore the gut microbial profiles, diagnostic value, and functional pathways in premenopausal breast cancer patients. Here, we analyzed 267 breast cancer patients with different menopausal statuses and age-matched female controls. The α-diversity was significantly reduced in premenopausal breast cancer patients, and the ß-diversity differed significantly between breast cancer patients and controls. By performing multiple analyses and classification, 14 microbial markers were identified in the different menopausal statuses of breast cancer. Bacteroides fragilis was specifically found in young women of premenopausal statuses and Klebsiella pneumoniae in older women of postmenopausal statuses. In addition, menopausal-specific microbial markers could exhibit excellent discriminatory ability in distinguishing breast cancer patients from controls. Finally, the functional pathways differed between breast cancer patients and controls. Our findings provide the first evidence that the gut microbiota in premenopausal breast cancer patients differs from that in postmenopausal breast cancer patients and shed light on menopausal-specific microbial markers for diagnosis and investigation, ultimately providing a noninvasive approach for breast cancer detection and a novel strategy for preventing premenopausal breast cancer.

Comprehensive Transcriptomic Analysis Identifies ST8SIA1 as a Survival-Related Sialyltransferase Gene in Breast Cancer.

Hypersialylation caused by the overexpression of sialyltransferases (STs) is a common feature in cancer that is associated with several characteristics of tumorigenesis. Thus, identifying cancer-associated STs is critical for cancer therapy. However, ST screening has been frequently conducted in cell line models. In this study, we conducted a comprehensive analysis of STs in the clinical database and identified the STs related with the survival of breast cancer patients. RNA sequencing (RNA-Seq) data of 496 patients were obtained from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA). Of the eight mapped STs, ST3GAL5, and ST8SIA1 met the acceptable area under the curve (AUC) criteria for overall survival (OS). Using Kaplan-Meier methods, we determined that high expression of ST8SIA1 was associated with poor 10-year OS in all patients, triple-negative breast cancer (TNBC), and non-TNBC patients, and poor disease-free survival (DFS) rates particularly in TNBC. ST8SIA1 also had superior AUC values in terms of OS/DFS. High ST8SIA1 levels showed a higher risk for poor OS in different groups of patients and a higher risk for poor DFS particularly in TNBC. In summary, we conducted a comprehensive analysis of STs from the clinical database and identified ST8SIA1 as a crucial survival-related ST, which might be a potential therapeutic target for breast cancer and TNBC patients.

Akkermansia muciniphila is Negatively Correlated with Hemoglobin A1c in Refractory Diabetes.

Patients with refractory diabetes are defined as type 2 diabetes (T2D) patients; they cannot achieve optimal glycemic control and exhibit persistent elevations of hemoglobin A1c (HbA1c) ≥8% while on appropriate therapy. Hyperglycemia can lead to severe microvascular/macrovascular complications. However, in contrast to T2D, few studies have focused specifically on the gut microbiota in refractory diabetes. To examine this issue, we recruited 79 subjects with T2D and refractory diabetes (RT2D), and all subjects received standard therapy with Metformin or other hypoglycemic agents with or without insulin for at least one year. The α-diversity displayed no significant difference, whereas the ß-diversity showed a marginal significance (p = 0.054) between T2D and RT2D. The evaluation of taxonomic indices revealed reductions in both Akkermansia muciniphila and Fusobacterium and a corresponding enrichment of Bacteroides vulgatus, Veillonella denticariosi among those with RT2D. These microbial markers distinguished RT2D from T2D with an acceptable degree of discrimination (area under the curve (AUC) = 0.719, p < 0.01) and were involved in several glucose-related functional pathways. Furthermore, the relative abundance of Akkermansia muciniphila was negatively correlated with HbA1c. Our combined results reveal unique features of the gut microbiota in RT2D and suggest that the evaluation of the gut microbiota could provide insights into the mechanisms underlying glycemic control and the impact of therapeutic modalities in patients with RT2D.

Clinical Detection of Chronic Rhinosinusitis through Next-Generation Sequencing of the Oral Microbiota.

Chronic rhinosinusitis (CRS) is the chronic inflammation of the sinus cavities of the upper respiratory tract, which can be caused by a disrupted microbiome. However, the role of the oral microbiome in CRS is not well understood. Polymicrobial and anaerobic infections of CRS frequently increased the difficulty of cultured and antibiotic therapy. This study aimed to elucidate the patterns and clinical feasibility of the oral microbiome in CRS diagnosis. Matched saliva and nasal swabs were collected from 18 CRS patients and 37 saliva specimens from normal volunteers were collected for 16S rRNA sequencing. The α-diversity of the saliva displayed no significant difference between control and CRS patients, whereas the ß-diversity was significantly different (p = 0.004). Taxonomic indices demonstrated that Veillonella dispar, Rothia mucilaginosa, and Porphyromonas endodontalis were enriched, while Campylobacter and Cardiobacterium were reduced in the saliva of CRS patients. These microbial markers could significantly distinguish CRS patients from control (AUC = 0.939). It is noted that the 16S rRNA results of the nasal swab were consistent with the nasopharynx aerobic culture, and additionally detected multiple pathogens in CRS patients. In summary, these results indicated these oral microbiomes may provide a novel signal for CRS detection and that NGS may be an alternative approach for CRS diagnosis.

Resveratrol treatment improves the altered metabolism and related dysbiosis of gut programed by prenatal high-fat diet and postnatal high-fat diet exposure.

A maternal high-fat (HF) diet sensitizes offspring to the adverse effects of postnatal HF intake and can lead to metabolic dysregulation. Resveratrol, a natural polyphenolic compound found in grapes and red wine, could help to relieve metabolic syndrome dysregulation. Since the gut microbiota is known to be closely related to metabolic homeostasis, this study aimed to investigate the impact of a combination of maternal and postweaning HF diets on the gut microbiota and whether resveratrol could relieve the gut dysbiosis associated with metabolic dysregulation. Sprague-Dawley dams were sustained on either a chow or HF diet before mating, during pregnancy and during lactation. Their offspring were randomly fed chow or a HF diet after weaning. Four experimental groups were generated: CC (maternal/postnatal chow diet), HC (maternal HF/postnatal chow diet), CH (maternal chow/postnatal high-fat diet) and HH (maternal/postnatal HF diet). A fifth group consisted of HH with resveratrol treatment. We found that both maternal and postnatal HF exposure has a distinct effect on the gut microbiota metagenome of offspring. Maternal HF diet exposure decreased plasma acetate, propionate and butyrate level, while postnatal HF diet exposure decreased plasma acetate level in adult life. The metabolic dysregulation programed by the maternal and postnatal HF diets was related to the relevant gut microbiota. Resveratrol treatment ameliorated the altered plasma propionate level related to maternal HF and postnatal HF diet treatment. Resveratrol treatment also improved most of the altered metabolic dysregulation and related dysbiosis programmed by maternal and postnatal HF diet exposure.