Increased MALAT1 Levels in Thyroid Cancer are Linked to Metabolic Reprogramming and Lymphatic Infiltration in Chilean population
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA (lncRNA) implicated in cancer progression. In thyroid cancer, MALAT1 has been proposed as a potential biomarker, but its role in disease progression remains incompletely understood. Here, we analyzed MALAT1 RNA levels in paired tumoral and adjacent non-tumoral thyroid samples from a Chilean patient cohort. We found a positive correlation of MALAT1 levels with lymphatic infiltration that was not replicated when modeling MALAT1 expression in a larger cohort obtained from the TCGA-THCA database. An exploratory RNA-seq comparison of one matched tumor-adjacent tissue pair confirmed higher tumor abundance of MALAT1 and the epithelial-to-mesenchymal transition-marker VIM, together with lower abundance of cell-adhesion gene PCDH10. To investigate the impact of MALAT1 on thyroid cancer and cellular metabolism, we targeted MALAT1 in the papillary thyroid cancer cell line TPC1. MALAT1 knock-down reduced proliferation and migration while enhancing mitochondrial respiration with no changes in glycolysis. Notably, although MALAT1 was not localized within mitochondria, its silencing modulated the expression of transcripts associated with mitochondrial dynamics and mitophagy. Consistent with these results, transcriptomic correlation analysis in the TCGA-THCA cohort showed that MALAT1 expression was largely uncoupled from oxidative phosphorylation and glycolysis gene programs, while negatively correlating with core regulators of mitophagy and mitochondrial dynamics, pointing to a link with mitochondrial quality control rather than direct bioenergetic reprogramming. Our findings highlight MALAT1 as a contributor to thyroid cancer aggressiveness and reveal a link between MALAT1 and mitochondrial quality control independent of direct mitochondrial localization. Besides, our results support a tissue-specific mechanism and population-specific role of MALAT1 in cancer biology.