London, Jan 29 : Scientists at the Winstar Institute have found two microRNAs (miRNAs) - miR-373 and miR-520c - that promote the spread of tumors, or metastasis.
Amongst the two, miR-373 may also give prior warning of metastatic breast cancer and the requirement for a hard-line treatment.
It has been shown that, if the translation of tumor suppressor genes is blocked, miRNAs will make possible the development of many types of cancer.
The study, led by Qihong Huang, M.D., Ph.D., an assistant professor in Wistar's Molecular and Cellular Oncogenesis Program, has shown the mechanism through which the two miRNAs completely changed non-invasive human breast cancer cells into rapidly metastasising cells in cell cultures and laboratory mice.
"Of the 450 miRNAs we tested, we found two, miR-373 and miR-520c, that induced cell migration in MCF-7 cells - a line of human breast cancer cells that normally does not metastasize," Nature quoted Huang, as saying.
The researchers identified miR-373 as a probable oncogene - gene causing cancer on modification -- in testicular cancer in 2006. Huang also said that miR-520c is a new miRNA whose function has not been known till date.
"Our most surprising finding is that miR-373 and isoforms of miR-520 are part of the same family. Their seed sequences, or first eight nucleotides, are all very similar. It suggests this family of miRNAs could target similar genes and have important biological and pathological functions in cancer development and metastasis," said Huang.
"They are not in normal testis, but are expressed in testicular cancer. We see them in breast cancer cells, especially metastatic cells, but not in normal breast cells," he added. When the researchers established metastasis-inducing properties of the miRNAs, they started searching for their target genes in MCF-7 cells.
After many experiments, the researchers narrowed their search down to a gene called CD44, containing genetic instructions for a common cell surface receptor molecule.
CD44 is found in most cell types and affects inter-cell as well as intra-cell interactions involving their microenvironments. It may also inhibit tumor metastasis.
It was discovered that on downregulating CD44, non-metastatic MCF-7 cells became metastatic.
The researchers found that when they injected MCF-7 cells without CD44 into immunodeficient mice, the mice developed bone and lung tumors, while mice receiving MCF-7 cells with CD44 did not.
"We found that miR-373 and miR-520c interfered with the expression of CD44 in MCF-7 cells. We think there are additional targets involved, but our results suggest that these miRNAs promote cell metastasis at least in part by limiting the expression of CD44," said Huang.
At the final level of the study, the scientists examined 11 pairs of primary and metastatic breast cancer tissue samples from cancer patients. It was discovered that metastatic tumors taken out from lymph nodes contained more miR-373 than the primary breast tumor from the same patient.
In another study of 72 human primary breast tumors, the scientists found higher mean expression of miR-373, and lower mean expression of CD44, in primary tumors from patients whose cancer had spread to their lymph nodes, as compared to patients whose tumors had not spread.
Huang said that such findings indicate that miR-373 can potentially become an important early biomarker for metastatic breast cancer.
"As far as we know, miR-373 is not expressed in normal tissue. So if we detect miR-373 in lymph nodes when a patient's breast tumor is removed, it would indicate that cancer cells have spread and the patient will need more aggressive therapy," said Huang.
The study will be published in Nature Cell Biology and is available online.