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Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity
Published on: January 7, 2019
MALT1 Inhibition of Oral Carcinoma Cell Invasion and ERK/MAPK Activation
T Chiba1, Y Soeno2, Y Shirako2
1Department of Biochemistry, School of Life Dentistry at Tokyo, The Nippon Dental University, Tokyo, Japan.
Abstract:
The expression of mucosa-associated lymphoid tissue 1 (MALT1) that activates nuclear factor (NF)-κB in lymphocyte lineages is rapidly inactivated in oral carcinoma cells at the invasive front and the patients with worst prognosis. However, its mechanism to accelerate carcinoma progression remains unknown, and this study was carried out to examine the role in invasion. HSC2 oral carcinoma cells stably expressing wild-type MALT1 (wtMALT1) reduced the invasion of basement membrane matrices and collagen gels, and the dominant-negative form (∆MALT1)-expressing cells aggressively invaded into collagen gels. MALT1 decelerated proliferation and migration of cells and downregulated expression of matrix metalloproteinase 2 and 9, which were confirmed by short interfering RNA transfections. Reporter assays and immunoblot analysis showed that MALT1 does not affect the NF-κB pathway but inhibits ERK/MAPK activation. This was confirmed by endogenous MALT1 expression in oral carcinoma cell lines. Orthotopic implantation of ∆MALT1-expressing HSC2 cells in mice grew rapid expansive and invasive tongue tumors in contrast to an absence of tumor formation by wtMALT1-expressing cells. These results demonstrate that MALT1 suppresses oral carcinoma invasion by inhibiting proliferation, migration, and extracellular matrix degradation and that the ERK/MAPK pathway is a target of MALT1 and further suggests a role as a suppressor of carcinoma progression.
Insights
Mucosa-associated lymphoid tissue 1 (MALT1) suppresses oral carcinoma invasion by inhibiting cell proliferation, migration, and matrix degradation. MALT1 targets the ERK/MAPK pathway, acting as a suppressor of oral cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Mucosa-associated lymphoid tissue 1 (MALT1) is crucial for NF-κB activation in lymphocytes.
- MALT1 expression is reduced in oral carcinoma at the invasive front, correlating with poor prognosis.
- The precise mechanism by which MALT1 influences oral cancer progression remains unclear.
Purpose of the Study:
- To investigate the role of MALT1 in oral carcinoma invasion and progression.
- To elucidate the molecular pathways targeted by MALT1 in oral cancer cells.
Main Methods:
- Stable expression of wild-type (wtMALT1) and dominant-negative (∆MALT1) MALT1 in HSC2 oral carcinoma cells.
- Invasion assays using basement membrane matrices and collagen gels.
- Short interfering RNA (siRNA) transfections to confirm gene downregulation.
- Reporter assays and immunoblot analysis to assess pathway activation.
- Orthotopic implantation of modified cells in mouse models.
Main Results:
- wtMALT1 expression reduced cell invasion, proliferation, and migration.
- ∆MALT1 expression led to aggressive invasion into collagen gels.
- MALT1 downregulated matrix metalloproteinase 2 and 9 (MMP2/9) expression.
- MALT1 inhibited ERK/MAPK activation, independent of the NF-κB pathway.
- In vivo studies showed wtMALT1 suppressed tumor formation, while ∆MALT1 promoted rapid, invasive tumor growth.
Conclusions:
- MALT1 acts as a suppressor of oral carcinoma invasion and progression.
- MALT1 inhibits proliferation, migration, and extracellular matrix degradation.
- The ERK/MAPK pathway is a key target inhibited by MALT1 in oral cancer.
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