July 15, 2022 -- Moffitt Cancer Center researchers have challenged the widely held view that protein structure and function are the key drivers of cancer development.
Their study, details of which were published July 14 in Cancer Research, found competitive endogenous RNA (ceRNA) drive melanoma growth and metastasis by blocking the antitumor activity of other molecules.
Based on the findings, the researchers see opportunities to expand cancer drug development beyond the current focus on DNA and protein alterations to improve treatment of melanoma and other tumor types.
Changes in DNA can alter the structure and function of proteins and, in doing so, drive the development of tumors. Current cancer drug development programs are built on that established fact. More recently, researchers have shown that RNA, the intermediary molecules between DNA and proteins, can also play a role in the pathogenesis of cancer.
Changes to microRNA (miRNA), molecules that silence protein-coding RNA, can contribute to tumor development. Recent studies have built on that knowledge, showing that ceRNA can bind to miRNA molecules to block their function.
While ceRNA was discovered more than a decade ago, and was quickly identified as a potential player in tumor growth, researchers are still working to understand its role in the development of cancer. Now, the Moffitt team has contributed to that effort by analyzing melanoma chromosome alterations. The study revealed that gains in chromosome segment 1q were very common in metastatic melanoma cases.
Drilling down, the researchers showed that chromosome 1q gains promote the progression and metastasis of melanoma through the overexpression of three ceRNAs: CEP170, NUCKS1, and ZC3H11A. The molecules sequestered or "soaked up" miRNAs that suppress tumors, thereby promoting cell growth, migration, and invasion in melanoma cell lines and enhancing melanoma metastasis in mouse models.
"Our study challenges the notion that somatic copy number alterations promote cancer predominantly through their encoded proteins and establishes ceRNAs as potent drivers underlying the oncogenicity of somatic copy number alterations," said Florian Karreth, PhD, study author and assistant member of Moffitt's molecular oncology department, in a statement.
The study focused on melanoma but found evidence that similar processes may drive other tumor types. The three ceRNAs implicated in the growth of melanoma were also found in tumors of the breast, colon, liver, and lung. With the discovery of the three ceRNAs in other tumors, the researchers postulated that chromosome 1q ceRNA deregulation is a common driver of cancer progression.