chondroitin-sulfates and Adenocarcinoma-of-Lung

Lung cancer is one of the most common types of cancer with limited therapeutic options, therefore a detailed understanding of the underlying molecular changes is of utmost importance. In this pilot study, we investigated the proteomic and glycosaminoglycan (GAG) profile of ALK rearranged lung tumor tissue regions based on the morphological classification, mucin and stromal content. Principal component analysis and hierarchical clustering revealed that both the proteomic and GAG-omic profiles are highly dependent on mucin content and to a lesser extent on morphology. We found that differentially expressed proteins between morphologically different tumor types are primarily involved in the regulation of protein synthesis, whereas those between adjacent normal and different tumor regions take part in several other biological processes (e.g. extracellular matrix organization, oxidation-reduction processes, protein folding) as well. The total amount and the sulfation profile of heparan sulfate and chondroitin sulfate showed small differences based on morphology and larger differences based on mucin content of the tumor, while an increase was observed in both the total amount and the average rate of sulfation in tumors compared to adjacent normal regions.

Topics: Adenocarcinoma of Lung; Chondroitin Sulfates; Glycosaminoglycans; Heparitin Sulfate; Humans; Lung Neoplasms; Mucins; Pilot Projects; Proteomics; Receptor Protein-Tyrosine Kinases

The abnormal modification of chondroitin sulfate is one of the leading causes of disease, including cancer progression. During chondroitin sulfate biosynthesis, the CHST11 enzyme plays a vital role in its modification, but its role in cancer is not fully understood. Therefore, understanding the relationship between CHST11 and pulmonary-related diseases through clinically relevant information may be useful for diagnosis or treatment.. A variety of pulmonary fibrosis clinical gene expression omnibus (GEO) datasets were used to assess the association between CHST11-related manifestations and fibrosis. Multiple lung cancer-related databases, including The Cancer Genome Atlas, GEO datasets, UCSC Xena, GEPIA2, Cbioportal and ingenuity pathway analysis were used to evaluate the clinical correlation between CHST11 and lung cancer and potential molecular mechanisms. For drug repurposing prediction, the molecules that correlated with CHST11 were subjected to the LINCS L1000 algorithm. A variety of in vitro assays were performed to evaluate the in-silico models, including RNA and protein expression, proliferation, migration and invasion.. Clinical analyses indicate that the levels of CHST11 are significantly elevated in cases of pulmonary-related diseases, including fibrosis and lung cancer. According to multiple lung cancer cohorts, CHST11 is the only member of the carbohydrate sulfotransferase family associated with overall survival for lung adenocarcinomas, and it is highly related to smoking-induced lung cancer patients. Based on the results of in vitro experiments, CHST11 expression contributes to tumor malignancy and promotes multiple fibrotic activators. Correlation-based ingenuity pathway analysis indicated that CHST11-related molecules contributed to pulmonary fibrosis or lung adenocarcinomas via similar upstream stimulators. Based on known molecular regulatory relationships, CHST11 has been associated with the regulation of TGF-β and INFγ as important molecules contributing to fibrosis and cancer progression. Interestingly, WordCloud analysis revealed that CHST11-related molecules are involved in regulation primarily by integrin signaling, and these relationships were consistently reflected in the analysis of cell lines and the clinical correlation. A CHST11 signature-based drug repurposing analysis demonstrated that the CHST11/integrin axis could be targeted by AG-1478 (Tyrphostin AG 1478), brefeldin A, geldanamycin and importazole.. This study provides the first demonstration that CHST11 may be used as a biomarker for pulmonary fibrosis or lung cancer, and the levels of CHST11 were increased by TGF-β and INFγ. The molecular simulation analyses demonstrate that the CHST11/integrin axis is a potential therapeutic target for treating lung cancer.

Topics: Adenocarcinoma of Lung; Chondroitin Sulfates; Humans; Integrins; Lung Neoplasms; Pulmonary Fibrosis; Sulfotransferases; Transforming Growth Factor beta