Molecular Medicine Israel

Manipulating MicroRNA Levels May Return Cancer Cells to Normalcy

A possible approach for inducing cancer cells to revert to a precancerous state is based on the protein PLEKHA7 (Pleckstrin homology domain-containing family A member 7), which regulates the levels of select microRNAs (miRNAs) to suppress expression of cell transforming factors.

Investigators at the Mayo Clinic (Jacksonville, FL, USA) had been trying to explain why two proteins, E-cadherin and p120 catenin (catenin [cadherin-associated protein], delta 1 or p120) sometimes seemed to suppress cancer formation and at other times seemed to promote it.

Cadherins (named for “calcium-dependent adhesion”) are a class of type-1 transmembrane proteins. They play important roles in cell adhesion, ensuring that cells within tissues are bound together. They are dependent on calcium (Ca2+) ions to function, hence their name. Loss of E-cadherin function or expression has been implicated in cancer progression and metastasis. E-cadherin downregulation decreases the strength of cellular adhesion within a tissue, resulting in an increase in cellular motility. This in turn may allow cancer cells to cross the basement membrane and invade surrounding tissues.

The gene for p120 encodes a member of the Armadillo protein family, which function in adhesion between cells and signal transduction.

The investigators reported in the August 24, 2015, online edition of the journal Nature Cell Biology that PLEKHA7 recruited the so-called “microprocessor complex” (association of DROSHA and DGCR8 proteins) to a growth-inhibiting site (apical zonula adherens) in epithelial cells instead of sites at basolateral areas of cell–cell contact. If the microprocessor complex was recruited to a basolateral area instead of to the apical zonula adherens, miRNA regulation was disrupted, causing tumor growth. Restoring normal miRNA levels in tumor cells reversed that aberrant cell growth.

“We believe that loss of the apical PLEKHA7-microprocessor complex is an early and somewhat universal event in cancer,” said senior author Dr. Panos Anastasiadis, chairman of the department of cancer biology at the Mayo Clinic. “In the vast majority of human tumor samples we examined, this apical structure is absent, although E-cadherin and p120 are still present. This produces the equivalent of a speeding car that has a lot of gas (the bad p120) and no brakes (the PLEKHA7-microprocessor complex). By administering the affected miRNAs in cancer cells to restore their normal levels, we should be able to reestablish the brakes and restore normal cell function. Initial experiments in some aggressive types of cancer are indeed very promising.”

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