At USP’s IQ (Institute of Chemistry), research has identified genes associated with the proliferation of cancerous tumors of the pancreas, which are highly resistant to treatment. Using computer techniques, the scientists were also able to assign possible functions to the genes, such as the growth and migration of tumor cells, to be confirmed by laboratory experiments.
The results of the work will help define new targets for the treatment of cancer, as well as markers of residual or recurrent disease in treated patients. The findings of the study are presented in an article published in the scientific journal Cellular oncology May 14th.
“Pancreatic cancer is the seventh 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 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 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 genes active in pancreatic tumors, focusing on the identification of long non-coding 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 DNA”, explains the professor.
“We have identified lncRNA genes that play an oncogenic role, i.e. they contribute to tumor cell manifestation characteristics associated with tumor malignancy, such as high proliferation, ability to grow independently of tumor substrate, migration and invasion”, explains the professor.
The study analyzed all the 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-throughput sequencing,” Reis describes. “The data obtained from the sequencing were subjected to bioinformatics analysis to reconstruct the sequence of RNAs expressed in the pancreas and identify lncRNAs with aberrant expression in tumors compared to normal tissues.”
Functions
“From high-resolution sequencing of RNAs active in tumors and in normal pancreatic tissue, we have identified lncRNA ‘signatures’ that generate aberrant expression in tumors, hundreds of them unpublished, unpublished. described in the literature. Several of them are correlated with patient survival and value for making the prognosis of the disease in the clinic”, explains the professor.
“Functional analysis of a set of lncRNAs in pancreatic tumor cell lines showed that silencing these RNAs reduced tumor characteristics, such as proliferation, migration and invasion, confirming that it is acted oncogenic lncRNAs.”
Using a computational approach based on gene co-expression networks, the research assigned roles to several oncogenic lncRNAs, indicating likely biological processes where they act that can be confirmed experimentally. “We have validated this approach by showing that one of these RNAs, lncRNA UCA1, is necessary for DNA repair in tumor cells exposed to ionizing radiation”, specifies Reis.
The study will continue with the study 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 pancreatic tumors taken from patients and implanted in immunocompromised mice”, specifies the professor. “We also intend to assess the presence of lncRNA in exosomes, vesicles secreted by tumor cells and in biological fluids of patients with pancreatic cancer throughout treatment.”
“These experiments will be important to assess the potential of lncRNAs as therapeutic targets or as markers for the detection of residual or recurrent disease in patients with pancreatic cancer undergoing treatment,” emphasizes Reis. “Thus, in addition to advancing knowledge of the biology of these RNAs, the work also contributes to novel molecular targets for diagnosis and possible therapeutic interventions for disease control.”
The research was conducted at the Department of Biochemistry at IQ, with the collaboration of a multidisciplinary team consisting of biochemists, molecular and cellular biologists, bioinformatics specialists and physicians from different USP units, and the support of FAPESP (São Paulo State Research Support Foundation).
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 doctors of the institution.