Brazilian group identifies transcripts expressed in pancreatic cancer

A study published in Molecular Cancer has identified, for the first time, a correlation between highly malignant tumors and the expression of long non-coding RNAs. The study presents a gene expression profile that is correlated with the metastasis of pancreatic adenocarcinoma.

By Fábio de Castro
 
Agência FAPESP – A study performed by researchers from the Universidade de São Paulo (USP) describes, for the first time, the presence of long non-coding RNAs, transcripts of over 200 nucleotides that do not code for proteins, in pancreatic cancer samples.

The study, coordinated by Eduardo Reis from the USP Chemistry Institute (IQ) and Marcel Cerqueira Machado of the USP Medical School (FM) with FAPESP funding, was published in the journal Molecular Cancer under its Regular Publishing Support/Articles program.

The project is also associated with the thematic project titled, “Functional characterization of intronic non-coding RNAs expressed in the human genome”—of which Reis is the main researcher—that is coordinated by Sérgio Verjovski-Almeida, IQ-USP professor and co-author of the Molecular Cancer article.

Other contributors to the article were Márcia Kubrusly from FM-USP and Ana Tahira, Michele Faria, Bianca Dazzani, Rogério Fonseca and Vinicius Maracaja-Coutinho, all from IQ-USP. According to the authors, the project calls attention to the potential use of lncRNAs in the molecular diagnosis of pancreatic cancer. A late diagnosis, they say, is related to the high death rate of patients with the disease.

According to Reis, pancreatic cancer is one of the most lethal tumors that affects humans, with a survival rate of less than 1% at five years following diagnosis. Even though it is only the seventh most common type of tumor found in Brazil, the poor survival rate is the reason why there is great interest in understanding the molecular bases of pancreatic cancer and in developing new tools for its diagnosis and treatment.

“Even though it is not so prevalent, pancreatic cancer is a large concern because there are very few options for treatment. Early diagnosis is very difficult and, in general, when the tumor is detected, it is already in an advanced stage. Late diagnosis is practically a death sentence,” Reis told Agência FAPESP.

Because of this characteristic, few patients undergo surgery, making it very difficult to obtain tumor samples, says Reis. Because of this, he says, the participation of Machado’s group, which has been studying pancreatic cancer for decades and is seeking new markers associated with the disease, was fundamental to the study.

“The FM-USP group managed to gather a significant set of samples. We analyzed some 40 samples of normal pancreatic tissue, primary tumors and metastasized tumors, which is something very difficult to obtain,” said Reis.

Reis’ laboratory, in turn, studies lncRNAs; which, according to him, remain an unexplored frontier of the human genome. He states that even though only 2% of the genome codes for proteins, in recent years, many groups across the globe—including the group from IQ-USP—have documented that the largest part of the human genome is transcribed to generate lncRNAs.

“Even though the function of most of these molecules is still unknown, there are studies that show unequivocally that lncRNAs perform essential functions in eukaryotic cells,” Reis affirmed.

In the article published in Molecular Cancer, the researchers identified collections of lncRNAs that are expressed in pancreatic tissue and whose abundance correlates to the histology of the cancer—from the primary tumor to metastasis. “This discovery points to the relevance of this class of transcripts in biological processes related to malignant transformation and metastasis in pancreatic cancer,” Reis declared.

As many recent studies have shown that lncRNAs are involved in mechanisms central to the normal function of cells, scientists speculate that the transcripts are also involved in pathological processes.

“Some studies had already identified correlations between lncRNA and breast and lung cancer, but no one had investigated the relevance of their expression in pancreatic cancer. We found that they are significantly expressed in pancreatic tissues, and we managed to find specific lncRNA signatures with aberrant expression in pancreatic tumors,” Reis affirmed.

Reis says that this finding opens an important window of opportunity for the study of the biological roles of lncRNA in the malignant transformation of pancreatic cancer—that is, the mechanism that causes normal pancreatic cells to transform into tumor cells.

“Our work shows that lncRNA must play a relevant role in this transformation. We also found very clear signatures when we compared the pancreatic tumor and the metastasis. This suggests that maybe these transcripts are related not only to malignant transformation but also to the tumor’s progression,” he said.

Aside from the functional aspect of lncRNA, Reis points out that the study also took into account those aspects related to diagnosis. “Our future goal is to find markers able to identify small lesions early on, before they turn into tumors. Then we will be close to the dream of making very early diagnoses through tiny samples taken in a minimally invasive manner,” he declared.

The scientist states that it will be necessary to have access to more samples of malignant lesions to transform the discovery of lncRNA signatures into markers for early diagnosis. “It would be interesting to have access to pancreatic cysts, for example, or body fluids like blood from individuals with and without pancreatic cancer,” said Reis.

The article “Long non-coding intronic RNAs are differentially expressed in primary and metastatic pancreatic cancer”, by Eduardo Reis and others, can be read by Nature subscribers at www.molecular-cancer.com.