Estudio de los lncRNAs MDL1 y MDL1AS en diferentes tipos de tumores y su relevancia clínica en adenocarcinoma rectal

Cancer is the leading cause of death in the world, and it is estimated that the incidence of this disease will increase in the coming years. Among the most common types of cancer are breast, lung and colorectal cancer, while those with the highest mortality rates are lung, colorectal and liver cancer. The process by which a normal cell transforms into a tumor cell involves various changes in processes such as cell metabolism, cell proliferation and cell migration. In all these processes, the mitochondrion plays a fundamental role, since it is the organelle in charge of cell metabolism and also participates in communication with the nucleus, regulating different cellular functions. The processes occurring within the mitochondrion as well as nucleus-mitochondrion communication are regulated by different mechanisms. In this context, long non-coding RNAs (lncRNAs) play a prominent role, and new lncRNAs are continuously being discovered, as well as new functions for those we already know. In 2018, Gao et al. identified two new mitochondrial lncRNAs in the region known as D-loop, which they named Mitochondrial D-loop 1 (MDL1) and Mitochondrial D-loop 1 antisense (MDL1AS). These authors also observed that, when comparing normal and tumor liver samples, the latter showed a lower expression of MDL1AS compared to non-tumor tissue. Given these differences in expression, we investigated whether these variations were observed in other types of tumors and found that colon, rectal, lung and glioblastoma cancers follow the pattern described by Gao et al. but the opposite is true for breast and laryngeal cancers: the tumor sample shows a higher expression of MDL1AS. We also describe that metastases to the lung from primary breast tumors show lower expression of MDL1 and MDL1AS than the tumors themselves. Finally, in an in vivo model, using the HT-29 cell line to initiate tumor growth, we identified that the primary tumor and metastases present lower MDL1AS expression than the original HT-29 cells; however, when treating the metastases with chemotherapy, MLD1AS expression increased. Second, we set out to analyze the role played by these lncRNAs inside the cell. To do so, we used different colorectal cancer cell lines (HT-29 and HCT-116) and breast cancer cell lines (MCF-7 and MDA-MB-231), as well as different double-stranded interference RNAs (DsiRNAs) to knockdown MDL1AS expression and evaluate how this affects cell metabolism, proliferation and migration in the different cell models. In these knockdowns we observed how, in both colorectal cancer and breast cancer, respiration is decreased compared to control cells. It was also demonstrated that, in correlation with what was observed in the expression differences, HCT-116 (colon) knockdowns have a lower proliferation and migration, while those of MDA-MB-231 (breast) presented a higher proliferation and migration, always compared to unmodified cells. Finally, a collaboration was carried out with the Hospital Universitario San Pedro de Logroño and the Fundación Hospital de Calahorra to investigate the clinical significance of these lncRNAs as possible biomarkers in a cohort of 69 patients diagnosed with rectal adenocarcinoma. In this cohort it was seen that both MDL1 and MDl1AS can act as prognostic biomarkers, with patients with high expression having a longer survival. Furthermore, no correlations of these levels with age, KRAS mutations, smoking or other classical biomarkers were found, clearly indicating that the levels of these lncRNAs are independent biomarkers. Thus, our study demonstrates the wealth of relevant biological and clinical information to be found in the D-loop of mitochondria, a region that has remained underappreciated until now.

Grantor dc:publisher

Universidad de La Rioja (España)

Year dc:date

2025

Author dc:creator

• Garrido Rodriguez, Pablo

Contributors dc:contributor

• Martínez Ramírez, Alfredo (Universidad de La Rioja)

Statement dc:rights

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Language dc:language

spa

Repository record dc:identifier

https://dialnet.unirioja.es/servlet/oaites?codigo=381939

OAI identifier oai:identifier

oai:dialnet.unirioja.es:TES0000023181