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Characterization of Cell Membrane Extensions and Studying Their Roles in Cancer Cell Adhesion Dynamics
Published on: March 26, 2018
Reciprocal regulation of forkhead box C1 and L1 cell adhesion molecule contributes to triple-negative breast cancer
Fan Zhang1, Yue Xu2, Jiediao Lin2
1Oncology Research Laboratory, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China.
Purpose:
The potential of targeting forkhead box C1 (FOXC1) as a therapeutic approach for triple-negative breast cancer (TNBC) is promising. However, a comprehensive understanding of FOXC1 regulation, particularly upstream factors, remains elusive. Expression of the L1 cell adhesion molecule (L1CAM), a transmembrane glycoprotein associated with brain metastasis, was observed to be positively associated with FOXC1 transcripts. Thus, this study aims to investigate their relationship in TNBC progression.
Methods:
Publicly available FOXC1 and L1CAM transcriptomic data were obtained, and their corresponding proteins were analyzed in four TNBC cell lines. In BT549 cells, FOXC1 and L1CAM were individually silenced, while L1CAM was overexpressed in BT549-shFOXC1, MDA-MB-231, and HCC1937 cells. CCK-8, transwell, and wound healing assays were performed in these cell lines, and immunohistochemical staining was conducted in tumor samples.
Results:
A positive correlation between L1CAM and FOXC1 transcripts was observed in publicly available datasets. In BT549 cells, knockdown of FOXC1 led to reduced L1CAM expression at both the transcriptional and protein levels, and conversely, silencing of L1CAM decreased FOXC1 protein levels, but interestingly, FOXC1 transcripts remained largely unaffected. Overexpressing L1CAM resulted in increased FOXC1 protein expression without significant changes in FOXC1 mRNA levels. This trend was also observed in BT549-shFOXC1, MDA-MB-231-L1CAM, and HCC1937-L1CAM cells. Notably, alterations in FOXC1 or L1CAM levels corresponded to changes in cell proliferation, migration, and invasion capacities. Furthermore, a positive correlation between L1CAM and FOXC1 protein expression was detected in human TNBC tumors.
Conclusion:
FOXC1 and L1CAM exhibit co-regulation at the protein level, with FOXC1 regulating at the transcriptional level and L1CAM regulating at the post-transcriptional level, and together they positively influence cell proliferation, migration, and invasion in TNBC.
Insights
Forkhead box C1 (FOXC1) and L1 cell adhesion molecule (L1CAM) are co-regulated at the protein level in triple-negative breast cancer (TNBC). Together, FOXC1 and L1CAM enhance TNBC cell proliferation, migration, and invasion.
Area of Science:
- Molecular biology
- Cancer research
- Cell biology
Background:
- Forkhead box C1 (FOXC1) is a potential therapeutic target for triple-negative breast cancer (TNBC).
- Understanding upstream regulators of FOXC1 is crucial for TNBC treatment strategies.
- L1 cell adhesion molecule (L1CAM) expression correlates with FOXC1 and is implicated in brain metastasis.
Purpose of the Study:
- To investigate the regulatory relationship between FOXC1 and L1CAM in triple-negative breast cancer (TNBC) progression.
- To elucidate the roles of FOXC1 and L1CAM in TNBC cell proliferation, migration, and invasion.
Main Methods:
- Analysis of publicly available FOXC1 and L1CAM transcriptomic data.
- Assessment of FOXC1 and L1CAM protein levels in TNBC cell lines.
- Gene silencing and overexpression experiments in TNBC cell lines (BT549, MDA-MB-231, HCC1937).
- Functional assays including CCK-8, transwell, and wound healing assays.
- Immunohistochemical staining of human TNBC tumor samples.
Main Results:
- A positive correlation was observed between L1CAM and FOXC1 transcripts in public datasets.
- FOXC1 knockdown reduced L1CAM expression; L1CAM silencing decreased FOXC1 protein but not transcripts.
- L1CAM overexpression increased FOXC1 protein levels without affecting FOXC1 mRNA.
- Altered FOXC1 or L1CAM levels significantly impacted TNBC cell proliferation, migration, and invasion.
- Positive correlation between L1CAM and FOXC1 protein expression in human TNBC tumors.
Conclusions:
- FOXC1 and L1CAM are co-regulated at the protein level in TNBC.
- FOXC1 regulates L1CAM at the transcriptional level, while L1CAM influences FOXC1 post-transcriptionally.
- The FOXC1-L1CAM axis promotes TNBC cell proliferation, migration, and invasion.
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