Fancai Zeng

To study the effects of ERCC1 and NGFR on metastasis and prognosis of basal-like breast cancer, and construct a prognostic prediction model, initially to explore whether ERCC1 plays a role in BLBC metastasis through NGFR. RNA-seq was used to identify the metastasis-related gene NGFR associated with ERCC1. ERCC1 and NGFR were transfected into BLBC cells, then western blot and transwell assays were applied to explore the effects of ERCC1 and NGFR on the migratory/invasive abilities and whether ERCC1 plays a role in BLBC cell metastasis through the NGFR. Data from the TCGA database were used to analyze the relationship between NGFR and ERCC1 expression in BLBC patients. The effects of ERCC1 and NGFR on the prognosis were analysed using K–M survival curves and multifactorial Cox regression, and a prognostic prediction model was constructed. RNA-seq results showed that NGFR was a differentially expressed gene of ERCC1, and NGFR was associated with ERCC1.After knockdown of ERCC1, the migratory and invasive abilities of cancer cells were significantly reduced; after overexpression of NGFR, the migratory and invasive abilities of cancer cells were significantly enhanced. In ERCC1 knockdown cancer cells, the expression levels of NGFR were subsequently reduced, and overexpression of NGFR resulted in an increase in migrating and invading cells and a rebound in migration and invasion capacity. NGFR was positively correlated with ERCC1 expression levels in BLBC patients (rs = 0.24, P < 0.05). The overall survival of patients in the group with high expression of ERCC1 and NGFR was shorter. High expression of ERCC1 (HR = 2.310, 95% CI 1.008 ~ 5.293) and NGFR (HR = 2.600, 95% CI 1.126 ~ 6.002) were independent risk factor for poor outcome. The prognostic prediction model’s C-index was 0.781, and the AUC values of 3-year and 5-year survival were 0.76, 0.81, and the calibration curves for 3-year and 5-year survival were close to the reference line. The accuracy of the model was similarly validated in the METABRIC dataset. A positive correlation was observed between ERCC1 and NGFR. ERCC1 may affect the migration and invasion ability of BLBC cells through NGFR; ERCC1 and NGFR were independent risk factors for the poor prognosis of BLBC patients and had a predictive effect on the 3-year and 5-year prognosis of BLBC.

Background: Breast cancer (BC) has become the main malignant tumor threatening the health of women worldwide. Previous studies have reported that Lactate dehydrogenase-A (LDHA) has critical roles in cancer development and progression. We aimed to explore the roles of LDHA and LDH5 isoenzyme activity in BC, which provides a new insight into LDHA for the treatment of BC. Methods: The expression of LDHA in BC and its relationship with clinicopathological features were obtained from various databases including The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA), Breast Cancer-Gene Expression Miner (bc-GenExMiner), TNMplot, UALCAN. The Kaplan‒Meier Plotter was used to evaluate the prognostic value of LDHA. Western blot was performed to detect LDHA expression. Agarose gel electrophoresis was performed to detect the activities of LDH isoenzymes. The in vitro proliferation, migration and invasion potentials of BC cells were evaluated using MTT assays, colony formation, wound-healing assay, matrix metalloproteinase assays and transwell assays, respectively. The activities of LDH isoenzymes in serum and tissues were measured in patients with BC and healthy controls. Results: Compared to normal tissues, LDHA expression was significantly higher in BC tissues. Patients’ nodal status, histological types, TP53 mutation status and PAM50 subtypes were significant factors influencing the LDHA expression. By overexpressing or silencing LDHA gene in BT549 cells, it was confirmed that LDHA promoted cell proliferation, migration and invasion. LDH5 isoenzyme activity in patients with BC was higher than healthy controls. The increased activity of LDH5 isoenzymes was induced by overexpression of LDHA in BC. High expression of LDHA was found to be associated with poor prognosis in BC. Conclusion: LDHA plays a critical role in the progression of BC through the regulation of the activity of LDH5 isoenzyme, indicating that LDHA may serve as a valuable target for BC treatment.

Hypoxia-inducible factors (HIFs) are essential transcription factors that orchestrate cellular responses to oxygen deprivation. HIF-1α, as an unstable subunit of HIF-1, is usually hydroxylated by prolyl hydroxylase domain enzymes under normoxic conditions, leading to ubiquitination and proteasomal degradation, thereby keeping low levels. Instead of hypoxia, sometimes even in normoxia, HIF-1α translocates into the nucleus, dimerizes with HIF-1β to generate HIF-1, and then activates genes involved in adaptive responses such as angiogenesis, metabolic reprogramming, and cellular survival, which presents new challenges and insights into its role in cellular processes. Thus, the review delves into the mechanisms by which HIF-1 maintains its stability under normoxia including but not limited to giving insights into transcriptional, translational, as well as posttranslational regulation to underscore the pivotal role of HIF-1 in cellular adaptation and malignancy. Moreover, HIF-1 is extensively involved in cancer and cardiovascular diseases and potentially serves as a bridge between them. An overview of HIF-1-related drugs that are approved or in clinical trials is summarized, highlighting their potential capacity for targeting HIF-1 in cancer and cardiovascular toxicity related to cancer treatment. The review provides a comprehensive insight into HIF-1’s regulatory mechanism and paves the way for future research and therapeutic development.

The components of the extracellular matrix (ECM) are dynamic, and they mediate mechanical signals that modulate cellular behaviors. Disruption of the ECM can induce the migration and invasion of cancer cells via specific signaling pathways and cytokines. Metastasis is a leading cause of high mortality in malignancies, and early intervention can improve survival rates. However, breast cancer is frequently diagnosed subsequent to metastasis, resulting in poor prognosis and distant metastasis poses substantial hurdles in therapy. In breast cancer, there is notable tissue remodeling of ECM proteins, with several identified as essential components for metastasis. Moreover, specific ECM molecules, receptors, enzymes, and various signaling pathways play crucial roles in breast cancer metastasis, drug treatment, and resistance. The in-depth consideration of these elements could provide potential therapeutic targets to enhance the survival rates and quality of life for breast cancer patients. This review explores the mechanisms by which alterations in the ECM contribute to breast cancer metastasis and discusses current clinical applications targeting ECM in breast cancer treatment, offering valuable perspectives for future ECM-based therapies.

As one of the most prevalent malignant neoplasms among women globally, the optimization of therapeutic strategies for breast cancer has perpetually been a research hotspot. The tumor microenvironment (TME) is of paramount importance in the progression of breast cancer, among which the extracellular matrix (ECM) and hypoxia are two crucial factors. The alterations of these two factors are predominantly regulated by the Hippo signaling pathway, which promotes tumor invasiveness, metastasis, therapeutic resistance, and susceptibility. Hence, this review focuses on the Hippo pathway in breast cancer, specifically, how the ECM and hypoxia impact the biological traits and therapeutic responses of breast cancer. Moreover, the role of miRNAs in modulating ECM constituents was investigated, and hsa-miR-33b-3p was identified as a potential therapeutic target for breast cancer. The review provides theoretical foundations and potential therapeutic direction for clinical treatment strategies in breast cancer, with the aspiration of attaining more precise and effective treatment alternatives in the future.

Globally, breast cancer stands as the most prevalent form of cancer among women. The tumor microenvironment of breast cancer often exhibits hypoxia. Hypoxia-inducible factor 1-alpha, a transcription factor, is found to be overexpressed and activated in breast cancer, playing a pivotal role in the anoxic microenvironment by mediating a series of reactions. Hypoxia-inducible factor 1-alpha is involved in regulating downstream pathways and target genes, which are crucial in hypoxic conditions, including glycolysis, angiogenesis, and metastasis. These processes significantly contribute to breast cancer progression by managing cancer-related activities linked to tumor invasion, metastasis, immune evasion, and drug resistance, resulting in poor prognosis for patients. Consequently, there is a significant interest in Hypoxia-inducible factor 1-alpha as a potential target for cancer therapy. Presently, research on drugs targeting Hypoxia-inducible factor 1-alpha is predominantly in the preclinical phase, highlighting the need for an in-depth understanding of HIF-1α and its regulatory pathway. It is anticipated that the future will see the introduction of effective HIF-1α inhibitors into clinical trials, offering new hope for breast cancer patients. Therefore, this review focuses on the structure and function of HIF-1α, its role in advancing breast cancer, and strategies to combat HIF-1α-dependent drug resistance, underlining its therapeutic potential.

Lactate dehydrogenase A (LDHA) primarily catalyzes the conversion between lactic acid and pyruvate, serving as a key enzyme in the aerobic glycolysis pathway of sugar in tumor cells. LDHA plays a crucial role in the occurrence, development, progression, invasion, metastasis, angiogenesis, and immune escape of tumors. Consequently, LDHA not only serves as a biomarker for tumor diagnosis and prognosis but also represents an ideal target for tumor therapy. Although LDHA inhibitors show great therapeutic potential, their development has proven to be challenging. In the development of LDHA inhibitors, the key active sites of LDHA are emphasized. Nevertheless, there is a relative lack of research on the amino acid residues around the active center of LDHA. Therefore, in this study, we investigated the amino acid residues around the active center of LDHA. Through structure comparison analysis, five key amino acid residues (Ala30, Met41, Lys131, Gln233, and Ala259) were identified. Subsequently, the effects of these five residues on the enzymatic properties of LDHA were investigated using site-directed mutagenesis. The results revealed that the catalytic activities of the five mutants varied to different degrees in both the reaction from lactic acid to pyruvate and pyruvate to lactic acid. Notably, the catalytic activities of LDHA^M41G and LDHA^K131I were improved, particularly in the case of LDHA^K131I. The results of the molecular dynamics analysis of LDHA^K131I explained the reasons for this phenomenon. Additionally, the optimum temperature of LDHA^M41G and LDHA^Q233M increased from 35 °C to 40 °C, whereas in the reverse reaction, the optimum temperature of LDHA^M41G and LDHA^K131I decreased from 70 °C to 60 °C. These findings indicate that Ala30, Met41, Lys131, Gln233, and Ala259 exert diverse effects on the catalytic activity and optimum temperature of LHDA. Therefore, these amino acid residues, in addition to the key catalytic site of the active center, play a crucial role. Considering these residues in the design and screening of LDHA inhibitors may lead to the development of more effective inhibitors.

Ferroptosis is a recently discovered category of programmed cell death. It is much different from other types of cell death such as apoptosis, necrosis and autophagy. The main pathological feature of ferroptosis is the accumulation of iron-dependent lipid peroxidation. The typical changes in the morphological features of ferroptosis include cell volume shrinkage and increased mitochondrial membrane area. The mechanisms of ferroptosis may be mainly related to lipid peroxidation accumulation, imbalance in amino acid antioxidant system, and disturbance of iron metabolism. Besides, hypoxia-inducible factor (HIF), nuclear factor-E2-related factor 2 (Nrf2), and p53 pathway have been demonstrated to be involved in ferroptosis. At present, the molecular mechanisms of ferroptosis pathway are still unmapped. In this review, an outlook has been put forward about the crucial role of apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) in the regulation of ferroptosis. APEX1 plays an important role in the regulation of intracellular redox balance and can be used as a potential inhibitor of ferroptotic cell death. Bioinformatics analysis indicated that the mRNA level of APEX1 is decreased in cases of ferroptosis triggered by erastin. Besides, it was found that there was a significant correlation between APEX1 and genes in the ferroptosis pathway. We have discussed the possibility to employ APEX1 inducers or inhibitors in the regulation of ferroptosis as a new strategy for the treatment of various human diseases.

Parkinson’s disease (PD) is a common neurodegenerative disease in middle-aged and elderly individuals. At present, no effective drug has been developed to treat PD. Although a variety of drugs exist for the symptomatic treatment of PD, they all have strong side effects. Most studies on PD mainly focus on dopaminergic neurons. This review highlights the function of glutamic acid transporters (GLTs), including excitatory amino acid transporters (EAATs) and vesicular glutamate transporters (VGLUTs), during the development of PD. In addition, using bioinformatics, we compared the expression of different types of glutamate transporter genes in the cingulate gyrus of PD patients and healthy controls. More importantly, we suggest that the functional roles of glutamate transporters may prove beneficial in the treatment of PD. In summary, VGLUTs and EAATs may be potential targets in the treatment of PD. VGLUTs and EAATs can be used as clinical drug targets to achieve better efficacy. Through this review article, we hope to enable future researchers to improve the condition of PD patients.

As an important enzyme for energy metabolism, lactate dehydrogenase (LDH) and its isoenzymes (LDH isoenzymes) have been extensively studied.