Gene stops tumors, but only when it’s gone

Losing one copy of DICER1 speeds cancer but cutting both copies halts spread

There are times when nothing at all is better than a half measure.

One of those times is when a cell becomes cancerous. The loss of one copy of a regulatory gene called DICER1 is enough to turn tumors deadly, while losing both can actually stop cancer, shows a new study led by researchers at MIT. The discovery, published online November 10 in Genes & Development, suggests that many other genes working at half capacity may also accelerate tumor growth.

The finding is a surprise because, normally, cells must lose both copies of tumor suppressor genes before cancer starts. One working copy is usually enough to protect cells.

DICER1 encodes a protein that helps slice long pieces of the genetic material RNA into small bits known as microRNAs. Despite their small size, microRNAs are now known to play a big role in controlling many cell functions, including regulating when and where proteins are made. Recently, microRNAs have been implicated in several types of cancer (SN: 6/11/05, p. 371).

Previously, the MIT team had shown that inhibiting the process of making microRNAs could lead to more virulent tumors in cells grown in lab dishes. In the new study, the researchers examined whether removing a single copy of DICER1 could have an effect on cancer development in mice.

Mice predisposed to lung cancer got more tumors when researchers removed one copy of the DICER1 gene from lung cells, the team found. Surprisingly, mice lacking both copies of the gene in their lungs fared better than mice with a single copy of the gene. The same was true for mice with another type of cancer called soft-tissue sarcoma: mice entirely lacking DICER1 survived better than mice with one working copy of the gene.

DICER1 may be an example of an unusual kind of tumor suppressor, one in which losing only one copy of a gene can promote tumor growth, says Tyler Jacks, a cancer biologist at MIT who led the study. Jacks calls such cases “haploinsufficient tumor suppressor genes,” meaning that two copies of the gene protect cells from cancer, but incapacitating one copy of a gene is enough to support tumor growth.

Other researchers may quibble with that term, says Clifford Steer, a geneticist and cell biologist at the University of Minnesota in Minneapolis. He says the term implies that a single copy of the gene should protect against cancer, exactly the opposite of what the data show.

“I’m still confused by the semantics,” Steer says. But there is no doubt that DICER1 is doing something important in cells, perhaps even something that goes beyond microRNA processing, he says. “It’s a great paper, but it raises more questions than it answers in terms of what causes cancer progression.”

Jacks’ team also showed that big chunks of DNA, including DICER1 and surrounding genes, are missing from about 20 percent to 30 percent of human cancers of the breast, kidney, large intestine, liver, lung, ovaries, pancreas and stomach. The researchers don’t have enough data to determine whether losing DICER1 leads to more aggressive cancers and poorer prognoses in people, Jacks says.

Many other genes, most not involved with microRNA processing, may also lead to more aggressive tumors when one copy is knocked out. Searches for cancer genes usually look for genes that follow the classical model, requiring both copies to be lost. Such searches should be refined to take into account genes like DICER1 that promote cancer when only a single copy is lost, Jacks says.

Even if researchers find such other genes, these genes may not follow DICER1’s pattern when both copies are lost. That’s because microRNAs are so crucial to a cell’s function that losing DICER1 or other parts of the manufacturing machinery could be disastrous for both healthy cells and tumor cells. Other genes may not be as crucial for cell survival as DICER1.

The research doesn’t offer any immediate solutions for cancer therapy. Wiping out both copies of the gene in tumor cells could prove toxic to healthy cells, and replacing a missing copy of the gene isn’t very practical, Jacks says.

Tina Hesman Saey

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.

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