RBM7 Deficiency Promotes Breast Cancer Metastasis by Regulating MFGE8 Splicing and NF-κB Pathway

Core Concepts

RBM7, an RNA-binding protein, suppresses breast cancer metastasis by controlling the alternative splicing of MFGE8 and inhibiting the NF-κB signaling pathway.

Abstract

The study reveals that the RNA-binding protein RBM7 plays a crucial role in regulating breast cancer metastasis. Key findings:

RBM7 expression is decreased in breast cancer metastases compared to primary tumors, and low RBM7 levels are associated with poor patient survival.

Depletion of RBM7 in breast cancer cells enhances their migratory, invasive, and angiogenic capabilities, leading to increased lung metastasis in mouse models.

Mechanistically, RBM7 controls the alternative splicing of MFGE8 pre-mRNA, favoring the production of the canonical isoform MFGE8-L. The truncated MFGE8-S isoform lacks the F5/8 type C domain and promotes cancer cell migration and invasion.

RBM7 knockdown also activates the NF-κB signaling pathway, leading to the upregulation of pro-angiogenic factors. Inhibition of NF-κB reverses the pro-angiogenic effects of RBM7 depletion.

The splicing shift of MFGE8 towards the MFGE8-S isoform is negatively correlated with RBM7 expression in breast cancer patient samples, and high MFGE8 exon 7 inclusion is associated with better patient survival.

In summary, the study demonstrates that RBM7 acts as a tumor suppressor in breast cancer by coordinating the alternative splicing of MFGE8 and modulating the NF-κB pathway, providing insights into the role of aberrant splicing in breast cancer metastasis.

Stats

"RBM7 expression positively correlates with overall survival and disease-free survival of breast cancer patients."
"RBM7 expression is decreased in breast cancer compared to normal tissues."
"Breast cancer cases with lymph node metastasis have lower RBM7 expression compared to cases without metastasis."
"RBM7 depletion in breast cancer cells enhances their migratory, invasive, and angiogenic capabilities, leading to increased lung metastasis in mouse models."
"RBM7 knockdown promotes the splicing switch of MFGE8 pre-mRNA from the canonical isoform MFGE8-L to the truncated isoform MFGE8-S."
"The proportion of MFGE8 exon 7 skipping is increased in breast cancer tissues compared to normal tissues, and is negatively correlated with RBM7 expression."

Quotes

"RBM7 is frequently reduced in a subset of breast cancer metastases from lymph nodes lesions and distant organ as compared to primary tumors."
"Breast cancer cells with loss of RBM7 gain enhanced aggressive capability and metastatic potential."
"RBM7 ablation enhanced the splicing switch of MFGE8 pre-mRNA from canonical isoform MFGE8-L to a truncated isoform MFGE8-S."
"RBM7 depletion-stimulated aggressiveness of breast cancer is dependent on MFGE8 splicing switch and NF-kB pathway activation."

Key Insights Distilled From

RBM7 deficiency promotes breast cancer metastasis by coordinating MFGE8 splicing switch and NF-kB pathway

by Huang,F., Da... at www.biorxiv.org 01-03-2024

https://www.biorxiv.org/content/10.1101/2024.01.03.574004v3

Deeper Inquiries

How might the regulation of other alternative splicing events by RBM7 contribute to breast cancer progression beyond the MFGE8 splicing switch

The regulation of alternative splicing events by RBM7 beyond the MFGE8 splicing switch could contribute to breast cancer progression through various mechanisms. RBM7 is known to impact the splicing of multiple genes involved in critical cellular processes such as cell cycle regulation, apoptosis, and DNA damage response. For example, RBM7 may influence the splicing of genes related to epithelial-mesenchymal transition (EMT), a key process in cancer metastasis. By altering the splicing patterns of genes involved in EMT, RBM7 could promote the acquisition of invasive and migratory properties in breast cancer cells. Additionally, RBM7-mediated splicing changes in genes related to angiogenesis, immune evasion, and extracellular matrix remodeling could further enhance the metastatic potential of breast cancer cells. The dysregulation of splicing events by RBM7 may lead to the expression of oncogenic isoforms or the loss of tumor-suppressive isoforms, ultimately driving tumor progression and metastasis.

What are the potential therapeutic strategies that could target the RBM7-MFGE8-NF-κB axis to combat metastatic breast cancer

Targeting the RBM7-MFGE8-NF-κB axis presents a promising therapeutic strategy to combat metastatic breast cancer. One potential approach is to develop small molecule inhibitors that specifically disrupt the interaction between RBM7 and its target pre-mRNA sequences, thereby preventing the splicing switch towards pro-metastatic isoforms like MFGE8-S. By inhibiting the production of oncogenic splicing variants, these inhibitors could potentially reduce the aggressiveness and metastatic potential of breast cancer cells. Additionally, targeting the NF-κB pathway with specific inhibitors or antagonists could help counteract the pro-inflammatory and pro-angiogenic effects induced by RBM7 depletion. Combination therapies that simultaneously target RBM7-mediated splicing events and NF-κB signaling may offer a synergistic approach to effectively suppress breast cancer metastasis.

Given the complex interplay between splicing regulation and transcriptional control, how might RBM7 also influence breast cancer metastasis through mechanisms beyond alternative splicing

Beyond its role in alternative splicing regulation, RBM7 may influence breast cancer metastasis through mechanisms involving transcriptional control and protein-protein interactions. RBM7 has been shown to interact with various transcription factors and chromatin modifiers, suggesting a potential role in gene expression regulation. By modulating the expression of genes involved in metastasis-related pathways, RBM7 could impact the phenotypic characteristics of breast cancer cells, such as their migratory and invasive properties. Additionally, RBM7-mediated protein-protein interactions with signaling molecules or transcriptional regulators may further modulate the metastatic behavior of breast cancer cells. The intricate crosstalk between splicing regulation, transcriptional control, and protein interactions highlights the multifaceted role of RBM7 in breast cancer metastasis.