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Updated: May 26, 2025
Impedance-based Real-time Measurement of Cancer Cell Migration and Invasion
Published on: April 2, 2020
IL6 mediated cFLIP downregulation increases the migratory and invasive potential of triple negative breast cancer
Samraj Sinha1, Rajdeep Roy1, Nilesh Barman1
1Department of Life Sciences, Presidency University, Kolkata, India.
Abstract:
c-FLIP (cellular FLICE-Like Inhibitor of Apoptotic protein) alias CFLAR (Cellular FADD-like apoptosis regulator) is an inhibitor of Caspase 8 and thus plays a key role in the regulation of extrinsic apoptotic pathway. However, the mechanisms of cFLIP regulation during the course of progression of cancer and it's involvement in tumour cell migration and invasion is yet to be known. Our TCGA data analysis has shown that cFLIP is downregulated in many cancers, including breast cancer, especially at the later stages. Next, we have analysed the role of cFLIP in breast cancer progression in In-vitro study. In doing so, we have used luminal breast cancer cell line MCF7 as non-aggressive and non-invasive breast cancer model and triple negative breast cancer cell lines MDA-MB-231, MDA-MB-468 and MDA-MB-453 as highly aggressive and invasive breast cancer cell model. When, we analysed and compared MCF7 and triple negative cell lines, we found a negative correlation between cFLIP expression pattern and metastasis which supported our In-silico study. Moreover, we found that Il6, one of the most prominent cytokines inside tumour microenvironment, helped in cFLIP downregulation via activation of p38 in MDA-MB-231 cell line. Not only that we have shown that cFLIP negatively regulated autophagy and this autophagy down-regulation resulted in decrease in metastasis. Thus, we have shown in an In-vitro model, for the first time, a complete interconnecting pathway in which IL6 mediated p38 activation directly influences metastasis by regulating autophagy via cFLIP downregulation.
Insights
Cellular FLICE-Like Inhibitor of Apoptotic protein (cFLIP) downregulation is linked to breast cancer progression and metastasis. Interleukin-6 (IL6) signaling reduces cFLIP, impacting autophagy and tumor cell invasion.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Cellular FLICE-Like Inhibitor of Apoptotic protein (cFLIP) regulates the extrinsic apoptotic pathway by inhibiting Caspase 8.
- The role of cFLIP in cancer progression, particularly in tumor cell migration and invasion, remains incompletely understood.
- TCGA data analysis revealed cFLIP downregulation in various cancers, including breast cancer, especially in advanced stages.
Purpose of the Study:
- To investigate the mechanisms of cFLIP regulation during cancer progression.
- To elucidate the role of cFLIP in breast cancer cell migration and invasion.
- To identify the molecular pathways linking tumor microenvironment factors to cFLIP expression and metastasis.
Main Methods:
- In-silico analysis using TCGA data for cFLIP expression patterns in different cancer stages.
- In-vitro studies using breast cancer cell lines (MCF7, MDA-MB-231, MDA-MB-468, MDA-MB-453) to model non-aggressive and aggressive phenotypes.
- Analysis of cytokine (IL6) and signaling pathway (p38) involvement in cFLIP regulation and its effect on autophagy and metastasis.
Main Results:
- A negative correlation was observed between cFLIP expression and metastasis in breast cancer cell lines, supporting in-silico findings.
- Interleukin-6 (IL6) downregulated cFLIP expression in MDA-MB-231 cells via p38 activation.
- cFLIP negatively regulates autophagy, and its downregulation leads to decreased metastasis.
Conclusions:
- IL6-mediated p38 activation downregulates cFLIP, which in turn suppresses autophagy.
- This pathway, involving IL6, p38, cFLIP, and autophagy, directly influences breast cancer metastasis.
- The study establishes a novel, interconnected molecular mechanism linking the tumor microenvironment to cancer cell invasion via cFLIP regulation.
