BACKGROUND: Temozolomide (TMZ) resistance is a significant challenge in treating glioblastoma (GBM). Collagen remodeling has been shown to be a critical factor for therapy resistance in other cancers. This study aimed to investigate the mechanism of TMZ chemoresistance by GBM cells reprogramming collagens. METHODS: Key extracellular matrix components, including collagens, were examined in paired primary and recurrent GBM samples as well as in TMZ-treated spontaneous and grafted GBM murine models. Human GBM cell lines (U251, TS667) and mouse primary GBM cells were used for in vitro studies. RNA-sequencing analysis, chromatin immunoprecipitation, immunoprecipitation-mass spectrometry, and co-immunoprecipitation assays were conducted to explore the mechanisms involved in collagen accumulation. A series of in vitro and in vivo experiments were designed to assess the role of the collagen regulators prolyl 4-hydroxylase subunit alpha 1 (P4HA1) and yes-associated protein (YAP) in sensitizing GBM cells to TMZ. RESULTS: This study revealed that TMZ exposure significantly elevated collagen type I (COL I) expression in both GBM patients and murine models. Collagen accumulation sustained GBM cell survival under TMZ-induced stress, contributing to enhanced TMZ resistance. Mechanistically, P4HA1 directly binded to and hydroxylated YAP, preventing ubiquitination-mediated YAP degradation. Stabilized YAP robustly drove collagen type I alpha 1 ( COL1A1) transcription, leading to increased collagen deposition. Disruption of the P4HA1-YAP axis effectively reduced COL I deposition, sensitized GBM cells to TMZ, and significantly improved mouse survival. CONCLUSION P4HA1 maintained YAP-mediated COL1A1 transcription, leading to collagen accumulation and promoting chemoresistance in GBM.
Temozolomide ; Humans ; Glioblastoma/drug therapy* ; Animals ; Mice ; Cell Line, Tumor ; Drug Resistance, Neoplasm/genetics* ; YAP-Signaling Proteins ; Hydroxylation ; Dacarbazine/pharmacology* ; Adaptor Proteins, Signal Transducing/metabolism* ; Transcription Factors/metabolism* ; Collagen/biosynthesis* ; Collagen Type I/metabolism* ; Prolyl Hydroxylases/metabolism* ; Antineoplastic Agents, Alkylating/therapeutic use*

OBJECTIVETo study the value of CT quantitativeness in the diagnosis of coal miner's pneumoconiosis.

METHODS104 cases were examined by HRCT scan at top of aortic arc, carina of trachea, 3 cm below the bifurcation of bronchi, among them there were 87 patients with different stages of coal miner's pneumoconiosis, 17 cases of normal males as the control group. All images were determined by CT density histogram at specific region (- 1,024-0 HU). Calculated the percentage of each pixel included a varying number of CT value, and the ratio of density values in the specific region.

RESULTSThe ratio of density values in the region of -983 (-) -778 HU was 87.31% in normal control group, and 80.51%, 75.27% and 72.99% respectively in the I, II, III stages of coal miner's pneumoconiosis. There were statistically significant differences among the groups (P < 0.01).

CONCLUSIONCT quantitative histogram information was able to observe the fibrosis and its degree of coal miner's pneumoconiosis. It has a good diagnostic value for its reliability and objectiveness.

Coal Mining ; Humans ; Pneumoconiosis ; diagnostic imaging ; Pulmonary Fibrosis ; diagnostic imaging ; Tomography, X-Ray Computed ; methods