Overexpression of a long noncoding RNA called MINCR causes many changes in expression levels of genes involved in cancer, according to a study published October 15 in Genomics, and its downregulation affects neurodegeneration-related genes. Finding a role for MINCR in both neurodegeneration and cancer hints at broad effects that lncRNAs are likely having in many pathological and developmental scenarios.
“There’s a lot of emerging data that connects brain cancer with normal developmental processes in the brain,” says John Prensner, a pediatric oncologist and researcher at Dana Farber Cancer Institute, Boston Children’s Hospital, and Harvard Medical School who was not involved in the study. “These [long noncoding] RNAs have multiple and flexible functions in different contexts,” he adds, “so one of the central strengths of the paper is to be able to start to tie together these different disease processes.”
Some estimates have put the number of kinds of human long noncoding RNAs (lncRNAs) at more than half a million, but researchers are far from understanding what—if anything—all those RNAs are doing. In a study published in 2018, Stella Gagliardi, the head of the RNA biology unit at the IRCCS Mondino Foundation in Italy, and colleagues found 293 lncRNAs, including MINCR, that were differentially expressed in the blood cells of patients with amyotrophic lateral sclerosis (ALS) and healthy controls.
When the researchers looked further into MINCR, they found that it was initially discovered in lymphoma tissue and previously implicated in other cancers, as well as Alzheimer’s disease. In their ALS sample, MINCR expression was lower than in controls. In tumors, though, the lncRNA is expressed at much higher levels than in healthy tissue. In the new study, the team set out to learn more about the function of MINCR, Gagliardi writes in an email to The Scientist.
The researchers analyzed the transcriptomes of normal human neuroblastoma cell lines and those where MINCR had been either knocked down or overexpressed. They found that overexpression changed the expression levels of 229 mRNAs, mostly transcripts of cancer-related genes, including those involved in pathways associated with p53 signaling, melanoma, and prostate cancer. On the other hand, knockdown led to expression changes in just 29 mRNA transcripts. The genes with the largest changes in expression levels after MINCR knockdown have been associated with both Alzheimer’s disease and ALS, indicating that downregulation of the lncRNA is related to neurodegeneration. Ten genes were shared between the two datasets—including two, ICAM1 and HMCN1, that were upregulated in both conditions and are involved in cell migration and communication.
“The highlights of the work are two: first, that the same long noncoding RNA can exert more than one mechanism of action depending on its transcriptional level and, secondly, that it can do it participating in really different diseases, such as neurodegeneration and cancer,” Cecilia Pandino, who participated in the research while a grad student at the University of Pavia in Italy and the IRCCS Mondino Foundation, writes in an email to The Scientist. Pandino, who is now a postdoc at the University of Milan, explains that neurodegeneration and cancer could be linked by deregulation of the same lncRNA in the opposite direction.
The choice of the neuroblastoma cell line “is important because not many studies [of lncRNAs] are done in neuronal models,” says George Calin, who investigates microRNAs in cancer at the University of Texas MD Anderson Cancer and was not involved in the work. Taking the work into other diverse cell lines and animal models will be important, he says, because researchers in the field need deeper investigation of noncoding RNA functions, which could lead to better understanding of “downstream target genes in order to identify the networks that can be targeted therapeutically.”
To that end, Gagliardi and colleagues are currently at work “to understand the cause and the functional consequences of MINCR deregulation through a full characterization both in cancer and in neurodegeneration,” she writes.
Correction (November 1): The first sentence of this article formerly stated that overexpression of MINCR cases changes in genes; in fact, it causes changes in the expression levels of genes, not genes themselves. The Scientist regrets the error.