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Published on: September 15, 2023
Simultaneous knockdown of uPA and MMP9 can reduce breast cancer progression by increasing cell-cell adhesion and
Anuradha Moirangthem1, Banashree Bondhopadhyay1, Mala Mukherjee2
1Molecular Biology and Human Genetics Laboratory, Department of Zoology, The University of Burdwan, Golapbag, Burdwan 713104, West Bengal, India.
Abstract:
In cancer progression, proteolytic enzymes like serine proteases and metalloproteinases degrade the basement membrane enabling the tumor cells to invade the adjacent tissues. Thus, invasion and metastasis are augmented by these enzymes. Simultaneous silencing of uPA and MMP9 in breast cancer cells decreased the wound healing, migratory, invasive and adhesive capacity of the cells. After simultaneous down regulation, cells were seen to be arrested in the cell cycle. There was a remarkable increase in the expression of cell to cell adhesion molecule E-cadherin, and decrease in Vimentin and Snail expression. In addition, there was a significant decrease in the expression of the stem cell marker Oct-4. In the breast tumor samples it has been observed that, tumors, expressing higher level of uPA and MMP9, express less amount of E-cadherin. It has also been observed that few tumors also show, Vimentin positive in the ductal epithelial area. Thus, our model can help for checking the aggressive tumor invasion by blocking of uPA and MMP9. Our present observations also give the concept of the presence of aggressive epithelial cells with mesenchymal nature in the tumor micro-environment, altering the expression of EMT genes.
Insights
Blocking urokinase-type plasminogen activator (uPA) and matrix metalloproteinase 9 (MMP9) in breast cancer cells reduces invasion and metastasis. This approach also impacts cell cycle, adhesion molecules, and stem cell markers, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Proteolytic enzymes like serine proteases and matrix metalloproteinases (MMP) are crucial in cancer progression, degrading the basement membrane and facilitating tumor cell invasion and metastasis.
- Urokinase-type plasminogen activator (uPA) and MMP9 are key enzymes implicated in augmenting cancer invasion and metastasis.
Purpose of the Study:
- To investigate the effect of simultaneous silencing of uPA and MMP9 on breast cancer cell behavior, including migration, invasion, adhesion, and cell cycle.
- To analyze the impact of uPA and MMP9 downregulation on the expression of epithelial-mesenchymal transition (EMT) markers and stem cell markers.
Main Methods:
- Simultaneous silencing of uPA and MMP9 in breast cancer cells.
- Assessment of wound healing, migratory, invasive, and adhesive capacities.
- Cell cycle analysis.
- Evaluation of E-cadherin, Vimentin, Snail, and Oct-4 expression levels.
- Analysis of breast tumor samples for uPA, MMP9, and E-cadherin expression correlation.
Main Results:
- Simultaneous downregulation of uPA and MMP9 significantly decreased wound healing, migration, invasion, and adhesion of breast cancer cells.
- Cells exhibited cell cycle arrest following simultaneous uPA and MMP9 silencing.
- Increased expression of E-cadherin (cell-to-cell adhesion molecule) and decreased expression of Vimentin and Snail were observed.
- A significant reduction in the stem cell marker Oct-4 was noted.
- Breast tumor samples showed an inverse correlation between high uPA/MMP9 levels and E-cadherin expression, with some tumors displaying Vimentin positivity in ductal epithelial areas.
Conclusions:
- Simultaneous blocking of uPA and MMP9 effectively inhibits aggressive tumor invasion and metastasis in breast cancer models.
- The findings suggest the presence of aggressive epithelial cells with mesenchymal characteristics within the tumor microenvironment, indicated by altered EMT gene expression.
- Targeting uPA and MMP9 presents a promising therapeutic strategy for controlling aggressive breast tumor invasion.
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