Targeting FTO induces colorectal cancer ferroptotic cell death by decreasing SLC7A11/GPX4 expression.

Ferroptosis is a newly identified iron-dependent form of death that is becoming increasingly recognized as a promising avenue for cancer therapy. N6-methyladenosine (m6A) is the most abundant reversible methylation modification in mRNA contributing to tumorigenesis. However, the crucial role of m6A modification in regulating ferroptosis during colorectal cancer (CRC) tumorigenesis remains elusive. Herein, we find that m6A modification is increased during ferroptotic cell death and correlates with the decreased m6A demethylase fat mass and obesity-associated protein (FTO) expression. Functionally, we demonstrate that suppressing FTO significantly induces CRC ferroptotic cell death, as well as enhancing CRC cell sensitivity to ferroptosis inducer (Erastin and RSL3) treatment. Mechanistically, high FTO expression increased solute carrier family 7 member 11 (SLC7A11) or glutathione peroxidase 4 (GPX4) expressions in an m6A-YTHDF2 dependent manner, thereby counteracting ferroptotic cell death stress. In addition, we identify Mupirocin as a novel inhibitor of FTO, and Mupirocin induces CRC ferroptosis and inhibits tumor growth. Clinically, the levels of FTO, SLC7A11, and GPX4, are highly correlated expression in CRC tissues. Our findings reveal that FTO protects CRC from ferroptotic cell death in promoting CRC tumorigenesis through triggering SLC7A11/GPX4 expression.

A prognostic nomogram for the cancer-specific survival of white patients with invasive melanoma at BANS sites based on the Surveillance, Epidemiology, and End Results database.

Objective: The purpose of this study was to develop a comprehensive nomogram for the cancer-specific survival (CSS) of white patients with invasive melanoma at back, posterior arm, posterior neck, and posterior scalp (BANS) sites and to determine the validity of the nomogram by comparing it with the conventional American Joint Committee on Cancer (AJCC) staging system. Methods: This study analyzed the patients with invasive melanoma in the Surveillance, Epidemiology, and End Results (SEER) database. R software was used to randomly divide the patients into training and validation cohorts at a ratio of 7:3. Multivariable Cox regression was used to identify predictive variables. The new survival nomogram was compared with the AJCC prognosis model using the concordance index (C-index), area under the receiver operating characteristic (ROC) curve (AUC), net reclassification index (NRI), integrated discrimination index (IDI), calibration plotting, and decision-curve analysis (DCA). Results: A novel nomogram was established to determine the 3-, 5-, and 8-year CSS probabilities of patients with invasive melanoma. According to the nomogram, the Age at Diagnosis had the greatest influence on CSS in invasive melanoma, followed by Bone Metastasis, AJCC, Stage, Liver Metastasis, Histologic Subtype, Brain Metastasis, Ulceration, and Primary Site. The nomogram had a higher C-index than the AJCC staging system in both the training (0.850 versus 0.799) and validation (0.829 versus 0.783) cohorts. Calibration plotting demonstrated that the model had good calibration ability. The nomogram outperformed the AJCC staging system in terms of AUC, NRI, IDI, and DCA. Conclusion: This was the first study to develop and evaluate a comprehensive nomogram for the CSS of white patients with invasive melanoma at BANS sites using the SEER database. The novel nomogram can assist clinical staff in predicting the 3-, 5-, and 8-year CSS probabilities of patients with invasive melanoma more accurately than can the AJCC staging system.

Enhanced cell affinity and osteogenic differentiation of liquid crystal-based substrate via surface bio-functionalization.

Regulation of cell-substrate interactions is an important factor for modulating cell behaviors. Tailoring the physical and chemical properties of the substrates to better mimic the extracellular matrix (ECM) of native tissue is a more effective strategy for enhancing the cell-substrate contact. In current work, we aim at improving surface bioactivity based on the liquid crystalline substrates for the enhancement in cell affinity and osteogenic differentiation. Polydopamine (PDOPA) adhesive coating was used as a reactive platform for the immobilization of chitooligosaccharide (COS) on the octyl hydroxypropyl cellulose ester (OPC) substrate to generate active OPC-PDOPA-COSs liquid crystalline substrates. Results demonstrated that PDOPA-coated OPC surfaces showed remarkably improved hydrophility and increased elastic modulus, leading to better initial cell attachment. Subsequent COS immobilization on the OPC-PDOPA layer could induce promotion of cell proliferation, polarization and cytoskeleton formation. Rat bone marrow mesenchymal stem cells (rBMSCs) seeded on the OPC-PDOPA-COSs showed higher alkaline phosphatase (ALP) activity, calcium deposition, and up-regulated bone-related genes expression, including BMP-2, RUNx-2, COL-I and OCN. In conclusion, surface biofunctionalization on the OPC-based liquid crystalline substrates could come into being the appropriate combination of surface chemistry and liquid crystalline characteristic that simulating in vivo ECM environment, resulting in a favorable support to enhance positive cell-substrate interactions.