New regulatory axis revealed for the cancer relevant matrix metalloprotease MMP14

Membrane-associated metalloprotease, MMP14, plays a significant role in different cancer tissues – for instance in breast cancer and melanoma patients high MMP14 levels increase the risk to develop metastasis. The study, conducted at the University of Helsinki, revealed that Prox1 negatively regulates MMP14 protein levels by suppressing transcription of the MMP14 gene.

Cancer and development are two different processes that surprisingly involve similar processes and regulatory circuits. With this premise, Silvia Gramolelli, a post-doctoral researcher in Professor Päivi Ojala's research group, University of Helsinki, uncovered a new regulatory axis for the membrane-associated metalloprotease, MMP14 (also named MT1-MMP).

When expressed on the surface of the cells, MMP14 eats up the extracellular matrix thus allowing the migration and invasion of the cells into the surrounding tissue. MMP14 participates in tissue remodelling during development and in physiological processes such as wound healing but it also plays a significant role in different cancer tissues, for instance in breast cancer and melanoma patients high MMP14 levels increase the risk to develop metastasis.

“The regulation of MMP14 levels is, thus, very important in both physiology and cancer and exploring how it is regulated is crucial for better understanding of these processes”, Gramolelli states.

Gramolelli investigated whether Prox1, a transcription factor instrumental for lymphatic endothelial cell specification, development of several organs and in colorectal cancer stem cells, is suppressing MMP14.

“This hypothesis stemmed from the observation that in different cancers and healthy tissues with high MMP14 very low or no Prox1 was expressed”, Professor Ojala explains.

Indeed, the study, published on June 22, 2018 in Scientific Reports, revealed that Prox1 negatively regulates MMP14 protein levels by suppressing transcription of the MMP14 gene. By manipulating Prox1 levels it was possible to modulate the amount of MMP14 in a plethora of systems and in a mouse model.

“The most surprising result was that by reintroducing Prox1 in highly invasive and metastatic breast cancer cells the ability of these cells to invade, the first step in metastasis formation, was inhibited”, Dr. Gramolelli tells. She continues:

“This research for the first time links Prox1 to MMP14 in a regulatory axis that occurs and contributes to several physiological and pathological processes and could provide new leads to many aspects of biomedical research.”

Translational cancer biology research program

For more information, please contact:

Silvia Gramolelli, PhD
University of Helsinki, Faculty of Medicine / Translational Cancer Biology Research Program
Phone: +358 29 412 5523
Email: silvia.gramolelli@helsinki.fi

Professor Päivi Ojala, PhD
University of Helsinki, Faculty of Medicine / Translational Cancer Biology Research Program
Phone: +358 29 415 9445
Email: paivi.ojala@helsinki.fi

Reference: PROX1 is a transcriptional regulator of MMP14. Silvia Gramolelli, Jianpin Cheng, Ines Martinez-Corral, Markus Vähä-Koskela, Endrit Elbasani, Elisa Kaivanto, Ville Rantanen, Krista Tuohinto, Sampsa Hautaniemi, Mark Bower, Caj Haglund, Kari Alitalo, Taija Mäkinen, Tatiana V. Petrova, Kaisa Lehti and Päivi M. Ojala. Scientific Reports 2018 Jun 22;8(1):9531.

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