At IQ (Institute of Chemistry) in the USP, research identified genes associated with the growth of pancreatic cancer tumors, which are highly resistant to treatment. Through computer techniques, scientists were able to assign potential functions to genes such as tumor cell growth and migration to be confirmed in laboratory experiments.
The results of the work will help determine new targets for cancer therapy as well as signs of residual or recurrence in treated patients. The findings of this study are presented in an article published in the scientific journal Cellular Oncology Last 14 May.
“Pancreatic cancer is the seventh leading cause of cancer death in Brazil and the world and one of the most deadly causes: the survival rate of patients is less than 5% five years after diagnosis. Currently, the only therapeutic option is surgical removal. Early stages of the disease” Professor Eduardo Mores Rego Race reported to the Journal da USP. “However, the absence of symptoms is difficult to diagnose early and when it is detected, it has already spread to other parts of the body. The cancer is still resistant to chemotherapy and immunotherapy.”
The research aims to create a high-resolution catalog of active genes in pancreatic tumors, focusing on the identification of long noncoding RNAs (IncRNAs). “The function of incRNAs is still not well understood by scientists, for example, messenger RNAs are responsible for the synthesis of proteins that express the genetic information contained in DNA,” the professor explains.
“We identified lncRNA genes that play an oncogenic role, meaning they contribute to tumor malignancy-related traits in tumor cells, such as high proliferation, substrate-independent growth potential, migration and invasion,” explains the professor.
The study analyzed 14 pancreatic tumors and a set of non-tumor pancreatic tissue genes (transcriptomes) from samples taken from patients.
“For this, all RNAs were isolated, then a library was created for the high-capacity sequence”, Race describes. “Bioinformatic analysis of the data obtained from sequencing was performed to reconstruct the sequence of RNA expressed in the pancreas and to identify lncRNAs with opposite expression in tumors compared to normal tissue.”
“In the high-resolution sequence of active RNAs in tumors and in normal pancreatic tissues, we identified the ‘signatures’ of lncRNAs in tumors that produce adverse expressions, hundreds of which are unpublished, not described in the literature. Many of them are related to patient survival. “, Says the professor.
“Functional analysis of the set of lncRNAs in pancreatic tumor cell lines showed that the silence of these RNAs reduced tumor characteristics, such as proliferation, migration, and invasion, confirming that they are oncogenic lncRNAs.”
Using a computer approach based on gene co-expression networks, research has assigned a role to several oncogenic lncRNAs, indicating potential biological processes where they operate and which can be confirmed experimentally. “We validated this approach by showing that one of these RNAs, lncRNA UCA1, is required for DNA repair in tumor cells exposed to ionizing radiation,” says Race.
The study will continue with the investigation of the effect of individual and combined silencing of oncogenic lncRNAs described in the work, will now be used in vivo tumor models.
“For this, we will use a collection of xenotum tumors already available in our laboratory, which were created from pancreatic tumors extracted from patients and implanted in immunosuppressed rats,” says the professor. “We intend to evaluate the presence of lncRNAs in the biological fluids of patients with exosomes, vesicles secreted by tumor cells, and pancreatic cancer during treatment.”
“These experiments will be important for evaluating the potential of lncRNAs as therapeutic targets or as markers for detecting residual or relapsing disease in patients undergoing treatment for pancreatic cancer,” emphasizes Race. “Thus, in addition to enhancing the biological knowledge of these RNAs, the function also contributes to new molecular targets for diagnosis and potential therapeutic interventions for disease control.”
The research was conducted in collaboration with a multidisciplinary team of biochemists, molecular and cellular biologists, bioinformatics experts and physicians from various units in the USP, and in the Department of Biochemistry at IQ. FAPESP (Research Support Foundation of Sao Paulo).
The clinical samples analyzed in the study were obtained from the biobank of the AC Camargo Cancer Center in Sओo Paulo, which also contributed to the organization’s physician work.