Hypoxic tumor microenvironment (TME) plays critical roles in induction of cancer stem cell-like phenotype in breast cancer and contribute to chemoresistance. However, the mechanism underlying stemness reprogramming of breast cancer cells (BCs) by hypoxic TME remains largely unknown. In the present study, we illustrated that HIF-2α, but not HIF-1α, induces stemness in BCs under hypoxia through SOD2-mtROS-PDI/GRP78-UPR^ER pathway, linking mitochondrial metabolic state to endoplasmic reticulum (ER) response via mitochondrial reactive oxygen species (mtROS) level. HIF-2α activates endoplasmic reticulum unfolded protein response (UPR^ER) in drug-sensitive MCF7 and T47D cells to induce drug-resistant stem-like phenotype. Genetic depletion or pharmacological inhibition (YQ-0629) of HIF-2α abolished hypoxia-induced stem-like phenotype in vitro and in vivo. Mechanistically, HIF-2α activates transcription of superoxide dismutase 2 (SOD2) under hypoxia and thereby decreases mtROS level. With less mtROS transported to endoplasmic reticulum, the expression and activity of protein disulfide isomerase (PDI) is suppressed, allowing glucose-regulated protein 78 (GRP78) to dissociate from receptor proteins of UPR^ER and bind misfolded protein to activate UPR^ER, which eventually confer chemoresistance and stem-like properties to BCs. Moreover, the increase in mtROS and PDI levels caused by HIF-2α knockdown and the subsequent UPR^ER inhibition could be substantially rescued by mitoTEMPOL (a mtROS scavenger), 16F16 (a PDI inhibitor), or GRP78 overexpression. Overall, we reported the critical roles of HIF-2α-SOD2-mtROS-PDI/GRP78-UPR^ER axis in mediating hypoxia-induced stemness in BCs, highlighting the interaction between organelles and providing evidence for further development of targeted HIF-2α inhibitor as a promising therapeutic strategy for chemoresistant breast cancer.

Breast cancer has been a worldwide burden of women’s health. Although concerns have been raised for early diagnosis and timely treatment, the efforts are still needed for precision medicine and individualized treatment. Radiomics is a new technology with immense potential to obtain mineable data to provide rich information about the diagnosis and prognosis of breast cancer. In our study, we introduced the workflow and application of radiomics as well as its outlook and challenges based on published studies. Radiomics has the potential ability to differentiate between malignant and benign breast lesions, predict axillary lymph node status, molecular subtypes of breast cancer, tumor response to chemotherapy, and survival outcomes. Our study aimed to help clinicians and radiologists to know the basic information of radiomics and encourage cooperation with scientists to mine data for better application in clinical practice.

GATA-binding protein 4 (GATA4) is recognized for its significant roles in embryogenesis and various cancers. Through bioinformatics and clinical data, it appears that GATA4 plays a role in breast cancer development. Yet, the specific roles and mechanisms of GATA4 in breast cancer progression remain elusive. In this study, we identify GATA4 as a tumor suppressor in the invasion and migration of breast cancer. Functionally, GATA4 significantly reduces the transcription of MMP9. On a mechanistic level, GATA4 diminishes MMP9 transcription by interacting with p65 at the NF-κB binding site on the MMP9 promoter. Additionally, GATA4 promotes the recruitment of HDAC1, amplifying the bond between p65 and HDAC1. This leads to decreased acetylation of p65, thus inhibiting p65’s transcriptional activity on the MMP9 promoter. Moreover, GATA4 hampers the metastasis of breast cancer in vivo mouse model. In summary, our research unveils a novel mechanism wherein GATA4 curtails breast cancer cell metastasis by downregulating MMP9 expression, suggesting a potential therapeutic avenue for breast cancer metastasis.

Introduction: In the era of rituximab, the NCCNIPI is widely used in clinical practice as a tool for the prognosis and risk stratification of diffuse large B-cell lymphoma (DLBCL). In recent years, FDG PET/CT has also shown unique prognostic value. We try to further confirm the prognostic role of metabolic parameters in the overall and subgroups patients. Methods: We retrospectively analysed 87 DLBCL patients who underwent baseline FDG PET/CT and followed the R-CHOP or R-CHOP-like strategy. The clinical parameters and PET-related metabolic parameters were evaluated. Results: For all patients, the 2-year PFS rate was 65.5% and the 2-year OS rate was 66.7%. According to Cox multivariate analysis, a high NCCNIPI score (4–8 points) and an MTV greater than 64.1 cm³ (defined by ROC) were independent prognostic factors for PFS and OS. The patients were divided into low, low-intermediate, high-intermediate and high-risk groups by NCCNIPI score. The 2-year PFS rates in each group were 90.9%, 71.3%, 33.2% and 16.7%, and the 2-year OS rates were 100%, 81.6%, 48.4% and 16.7%. In the subsequent subgroup analysis by MTV, it could further stratified low-intermediate and high-intermediate NCCNIPI groups, the P value was 0.068 and 0.069 for PFS, 0.078 and 0.036 for OS. Conclusions: MTV, as a tumor metabolic volume parameter, and the NCCNIPI score were independent predictors of prognosis in general DLBCL patients. In the low-intermediate and high-intermediate NCCNIPI subgroup, we further confirm the risk stratification abilities of MTV, which could add the prognostic value of NCCNIPI.

SET domain containing 5 (SETD5) is related to the aggressiveness of prostate and mammary cancers, but its association with non-small cell lung cancer (NSCLC) is unknown. Therefore, the purpose of this research was to determine the expression pattern and function of SETD5 in NSCLC. SETD5 was detected by immunohistochemical analysis in 147 patients with non-small cell lung cancer. SETD5 was overexpressed in A549 cells or suppressed with siRNA in H1299 cells. Wound healing and transwell assays were performed. The expression levels of SETD5, p-AKT/AKT, Snail, p-JNK/JNK, Slug, E-cadherin, Zo-1, p-P38/P38, occludin, α-catenin, p-ERK/ERK, and p-P90RSK/ P90RSK were assessed by western blot. Online analysis of overall survival in 1928 patients with NSCLC showed that the SETD5 gene was related to worse overall survival (OS)(P < 0.001). The positive expression rate of SETD5 in noncancerous tissues was lower than that in cancerous tissues (16.7% vs. 44.2%, P < 0.001). SETD5 was significantly correlated with advanced TNM stage (P < 0.001), lymph node metastasis (P < 0.001) and overall survival rate (P < 0.001). Overexpression of SETD5 in A549 cells increased migration and invasion, while deletion of SETD5 in H1299 cells decreased migration and invasion. After overexpression of SETD5, the expression of ZO-1 was downregulated, and that of Snail was upregulated. After overexpression of SETD5, the levels of p-ERK and its downstream factor p-p90rsk increased. These results suggest that SETD5 could regulate p-P90RSK and facilitate the migration and invasion of NSCLC and may be related to the poor prognosis of patients with NSCLC.