At the IQ (Institute of Chemistry) at USP, research identified genes associated with the proliferation of pancreatic cancer tumors, which are highly resistant to treatment. Through computational techniques, the scientists were also able to assign possible functions to genes, such as growth and migration of tumor cells, to be confirmed in laboratory experiments.
The results of the work will help define new targets for cancer therapy, as well as markers of residual or relapsing disease in treated patients. The study’s conclusions are presented in an article published in the scientific journal Cellular Oncology last May 14th.
“Pancreatic cancer is the seventh leading cause of cancer death in Brazil and in the world, and one of the deadliest: the survival of patients five years after diagnosis is less than 5%. Currently, the only curative treatment is surgical removal. in early stages of the disease”, reports Professor Eduardo Moraes Rego Reis, who coordinated the study, to Jornal da USP. “However, early diagnosis is difficult due to the absence of symptoms and, when it is detected, it has often already spread to other parts of the body. It is still a cancer resistant to chemotherapies and immunotherapies.”
The research aimed to generate a high-resolution catalog of active genes in pancreatic tumors, focusing on the identification of long noncoding RNAs (IncRNAs). “The functions of IncRNAs are still poorly understood by scientists, unlike, for example, messenger RNAs, responsible for the synthesis of proteins that will express the genetic information contained in the DNA”, explains the professor.
“We identified lncRNA genes that play an oncogenic role, that is, they contribute to the tumor cell manifesting characteristics associated with tumor malignancy, such as high proliferation, substrate-independent growth capacity, migration and invasion”, explains the professor.
The study analyzed the set of genes expressed (transcriptome) of 14 pancreatic tumors and non-tumor pancreatic tissue, from samples extracted from patients.
“For this, all RNAs were isolated, followed by the preparation of libraries for high-capacity sequencing”, describes Reis. “Data obtained from sequencing were subjected to bioinformatic analysis to reconstruct the sequence of RNAs expressed in the pancreas and identify lncRNAs with aberrant expression in tumors compared to normal tissue.”
Functions
“From high-resolution sequencing of active RNAs in tumors and in normal pancreatic tissue, we identified ‘signatures’ of lncRNAs that generate aberrant expression in tumors, hundreds of them unpublished, not described in the literature. Several of them are correlated with patient survival. and value to make prognosis of the disease in the clinic”, says the professor.
“Functional analysis of a set of lncRNAs in pancreas tumor cell lines showed that the silencing of these RNAs reduced tumor characteristics, such as proliferation, migration and invasion, confirming that they are oncogenic lncRNAs.”
Using a computational approach based on gene co-expression networks, the research assigned a role to several oncogenic lncRNAs, indicating the probable biological processes where they act and which can be confirmed experimentally. “We validated this approach by showing that one of these RNAs, the lncRNA UCA1, is necessary for DNA repair in tumor cells exposed to ionizing radiation”, says Reis.
The study will continue with the investigation of the effect of individual and combined silencing of the oncogenic lncRNAs described in the work, now using in vivo tumor models.
“For this, we will use a collection of xenotumors already available in our laboratory, generated from pancreas tumors removed from patients and implanted in immunosuppressed mice”, points out the professor. “We also intend to evaluate the presence of lncRNAs in exosomes, vesicles secreted by tumor cells, and in biological fluids of patients with pancreatic cancer throughout treatment.”
“These experiments will be important to evaluate the potential of lncRNAs as therapeutic targets or as markers for the detection of residual or relapsing disease in patients with pancreatic cancer undergoing treatment”, emphasizes Reis. “In this way, in addition to advancing knowledge about the biology of these RNAs, the work also contributes to new molecular targets for diagnosis and possible therapeutic interventions to control the disease.”
The research was carried out in the Department of Biochemistry at IQ, with the collaboration of a multidisciplinary team with biochemists, molecular and cellular biologists, bioinformatics specialists and physicians from different units at USP, and the support of FAPESP (Research Support Foundation of the State of São Paulo).
The clinical samples analyzed in the study were obtained from the biobank of the AC Camargo Cancer Center, in São Paulo, which also contributed to the work of the institution’s physicians.