Frontiers in Molecular Biosciences最新文献

The TEM8 protein coded by the ANTXR1 gene represents an emerging biomarker in solid tumors. In addition to the various roles TEM8 plays in oncogenesis, including angiogenesis, epithelial-to-mesenchymal transition, and cell migration, it has also been shown that the overexpression of the ANTXR1 gene in solid tumors correlates with poor prognostic indicators in several solid tumor histologies. As such, TEM8 has been identified as the target of novel oncologic therapies. It is especially attractive given its selective expression on the surface of solid tumor cells and associated stromal cells, such as cancer stem cells, invasive cancer cells, and immune cells, such as macrophages, angiogenic endothelial cells, pericytes, and cancer-associated fibroblasts. Furthermore, TEM8 plays this unique role as a mostly non-mutated gene in solid cancers. Here, we demonstrate that elevated expression of ANTXR1 in bladder cancer showed a statistical difference not only in overall survival (OS) but in progression-free survival (PFS), confirming the prognostic biomarker power of ANTXR1 expression.

Introduction: Patients with gastrointestinal cancers are prone to acute kidney injury (AKI) due to treatment or disease progression, and current diagnostic methods exhibit insufficient sensitivity and specificity. This study aims to evaluate the potential value of CDK1 and STAT1 in the diagnosis of AKI in this patient population.

Methods: A retrospective analysis was conducted on adjacent tissue, cancerous and the clinical data tissue from 150 gastrointestinal cancer patients treated at our hospital from May 2022 to May 2023. Differentially expressed genes (DEGs) associated with gastrointestinal cancer and kidney injury were identified through bioinformatics analysis. The expression of DEGs proteins in cancerous and adjacent tissues was assessed using immunohistochemical scoring (H scores). Patients were classified into AKI (n = 42) and non-AKI groups (n = 108) according to KDIGO AKI criteria. Univariate and multivariate logistic regression analyses were performed to investigate the influencing factors of AKI occurrence. Spearman correlation analysis was used to explore the relationship between DEGs and AKI biomarkers (Scr, BUN, MAU, and UA). The application value of DEGs in early diagnosis of AKI was evaluated using ROC curves.

Results: Bioinformatics analysis identified CDK1, STAT1, COL1A2, and COL1A1 as DEGs related to AKI in gastrointestinal cancer. Immunohistochemical analysis revealed elevated H scores for CDK1, STAT1, COL1A2, and COL1A1 in tumor tissues. Univariate analysis showed no significant differences in age, sex, marital status, education level, monthly income, disease type, cancer stage, or tumor markers (CEA, CA242, CA50) between AKI and non-AKI groups (P > 0.05). However, the AKI group exhibited significantly higher levels of MAU, UA, and H scores for CDK1, STAT1, COL1A2, and COL1A1 compared to the non-AKI group (P < 0.05). Multivariate logistic regression confirmed that MAU, UA, CDK1, and STAT1 are independent risk factors for AKI in gastrointestinal cancer patients. Correlation analysis indicated a significant positive association between CDK1, STAT1, and AKI biomarker levels (P < 0.05). ROC curve analysis demonstrated that CDK1 and STAT1 possess high diagnostic value for early detection of AKI in patients with gastrointestinal cancer, with enhanced efficacy when used in combination.

Conclusion: CDK1 and STAT1 serve as early diagnostic indicators for the occurrence of AKI in gastrointestinal cancer patients.

Cytokines play a crucial role in mediating cell communication within the tumor microenvironment (TME). Tumor-associated macrophages are particularly influential in the regulation of immunosuppressive cytokines, thereby supporting tumor metastasis. The upregulation of Th2 cytokines in cancer cells is recognized for its involvement in suppressing anticancer immunity. However, the association between these cytokines and tumor-secreted extracellular vesicles (EVs) remains poorly understood. Therefore, our objective was to investigate the connection between tumor-promoting macrophages and melanoma-derived EVs. The analysis from altered cytokine profile data showed that melanoma-derived EVs upregulate Th2 cytokine expression in naïve macrophages, thereby contributing to the promotion of tumor-supporting functions. Notably, many of these cytokines were also found to be upregulated in metastatic melanoma patients (n = 30) compared to healthy controls (n = 33). Overall, our findings suggest a strong connection between melanoma secretory EVs and the induction of tumor-associated macrophages that facilitates the development of an immunosuppressive TME, supporting melanoma metastasis through regulation at both local and systemic levels.

Introduction: Extracellular vesicles (EVs) shed from tumor cells into peripheral circulation or other body fluids are promising biomarkers for cancer diagnosis with enormously long circulation. Consequently, precise methods for differentiating normal and tumor-associated EVs (TAEs) are required.

Methods: This study used quantifiable antibody-DNA conjugate-assisted quantitative methods combined with proximity ligation technology to detect TAEs. The antibody-DNA conjugate contained one antibody associated with three oligonucleotides for signal amplification. The antibody in the conjugate can recognize the surface tumor antigens of TAEs. Simultaneously, DNA in the conjugate is attached to the surfaces of TAEs and holds the signal amplification post, converting protein identities to DNA amplification for protein detection, even at the molecular level.

Results: These findings revealed that TAEs can be quantitatively detected using DNA-mediated quantitative polymerase chain reaction (qPCR). Antibody-DNA conjugates were used to recognize the epithelial cell adhesion molecule (EpCAM) antigen on the TAE surface and quantify the antigen using qPCR for cancer analysis.

Discussion: This method proposed a new quantitative detection approach for TAEs, which aim to identify specific EV-associated markers for diagnostic or therapeutic, this method could inspire a new idea for tumor diagnosis and detection of other diseases.

Gene fusion events result in chimeric proteins that are frequently found in human cancers. Specific targeted therapies are available for several types of cancer fusions including receptor tyrosine kinase gene moieties. RNA sequencing (RNAseq) can directly be used for detection of gene rearrangements in a single test, along with multiple additional biomarkers. However, tumor biosamples are usually formalin-fixed paraffin-embedded (FFPE) tissue blocks where RNA is heavily degraded, which in theory may result in decreased efficiency of fusion detection. Here, for the first time, we compared the efficacy of gene fusion detection by RNAseq for matched pairs of freshly frozen in RNA stabilizing solution (FF) and FFPE tumor tissue samples obtained from 29 human colorectal cancer patients. We detected no statistically significant difference in the number of chimeric transcripts in FFPE and FF RNAseq profiles. The known fusion KANSL1-ARL17A/B occurred with a high frequency in 69% of the patients. We also detected 93 new fusion genes not mentioned in the literature or listed in the ChimerSeq database. Among them, 11 were found in two or more patients, suggesting their potential role in carcinogenesis. Most of the fusions detected most probably represented read-through, microdeletion or local duplication events. Finally, in one patient, we detected a potentially clinically actionable in-frame fusion of LRRFIP2 and ALK genes not previously described in colorectal cancer with an intact tyrosine kinase domain that can be potentially targeted by ALK inhibitors.

Introduction: Recombinant alpha-1 antitrypsin (AAT) therapy has been shown to have beneficial effects to mitigate the progression of various diseases. Here, we hypothesized that administration of pharmaceutical-grade human AAT (hAAT) is effective in mitigating hypertension induced by salt-loading in juvenile mice by reducing the concentration of diacylglycerols (DAGs) and activity of protein kinase C (PKC) in the kidney.

Methods: Four-week old 129Sv mice were salt-loaded to induce hypertension and then administered hAAT or vehicle.

Results: Administration of hAAT was found to significantly reduce high blood pressure in both the active and inactive cycles of the 129Sv hypertensive mice. A lipidomic analysis showed decreased concentrations of multiple diacylglycerols in kidney cortex membrane fractions from mice treated with hAAT compared to vehicle. PKC activity was less in the 129Sv mice that received hAAT compared to vehicle. Western blotting and immunohistochemistry analysis showed the density of the sodium-potassium-chloride co-transporter (NKCC2) was significantly reduced in kidney cortex membrane fractions of juvenile mice that received hAAT compared to vehicle.

Conclusion: Taken together, this study demonstrates a new protective effect of hAAT in normalizing blood pressure after the development of saltinduced hypertension in juvenile mice in a mechanism involving a decrease in NKCC2 membrane expression, presumably due to decreased levels of DAGs in the plasma membrane and a subsequent decrease in PKC activity.

Introduction: Ovarian cancer has been difficult to cure due to acquired or intrinsic resistance and therefore, newer or more effective drugs/approaches are needed for a successful treatment in the clinic. Erastin (ER), a ferroptosis inducer, kills tumor cells by generating and accumulating reactive oxygen species (ROS) within the cell, resulting in an iron-dependent oxidative damage-mediated ferroptotic cell death.

Methods: We have utilized human ovarian cancer cell lines, OVCAR-8 and its adriamycin-selected, multi-drug resistance protein (MDR1)-expressing NCI/ADR-RES, both equally sensitive to ER, to identify metabolic biomarkers of ferroptosis.

Results: Our studies showed that ER treatment rapidly depleted cellular glutathione and cysteine and enhanced formation of ophthalamate (OPH) in both cells. Opthalalmate has been proposed to be a biomarker of oxidative stress in cells. Our study also found significant decreases in cellular taurine, a natural antioxidant in cells. Additionally, we found that ER treatment decreased cellular levels of NAD+/NADP+, carnitines and glutamine/glutamate in both cells, suggesting significant oxidative stress, decrease in energy production, and cellular and mitochondrial disfunctions, leading to cell death.

Conclusion: Our studies identified several potential biomarkers of ER-induced ferroptosis including OPH, taurine, NAD+, NADP+ and glutamate in ovarian cancer cells. Identifying specific metabolic biomarkers that are predictive of whether a cancer is susceptible to ferroptosis will help us devise more successful treatment modalities.

Introduction: Kidney diseases pose a serious healthcare problem because of their high prevalence, worsening of patients' quality of life, and high mortality. Patients with kidney diseases are often asymptomatic until disease progression starts. Expensive renal replacement therapy options, such as dialysis or kidney transplant, are required for end-stage kidney disease. Early diagnosis of kidney pathology is crucial for slowing down or curbing further damage. This study aimed to analyze the features of the protein composition of blood plasma in patients with the most common kidney pathologies: kidney calculus, kidney cyst, and kidney cancer.

Methods: The study involved 75 subjects. Proteins associated with kidney pathologies (CFB, SERPINA3, HPX, HRG, SERPING1, HBB, ORM2, and CP) were proposed. These proteins are important participants of complement and coagulation cascade activation and lipid metabolism.

Results: The revealed phosphorylated proteoforms (CFB, C4A/C4B, F2, APOB, TTR, and NRAP) were identified. For them, modification sites were mapped on 3D protein models, and the potential role in formation of complexes with native partner proteins was assessed.

Discussion: The study demonstrates that the selected kidney pathologies have a similar proteomic profile, and patients can be classified into kidney pathology groups with an accuracy of (70-80)%.