Charged multivesicular body protein 7 as a prognostic biomarker in colorectal cancer metastasis

Abstract

Colorectal cancer (CRC) is a leading cause of cancer-related mortality, primarily due to tumor metastasis. A recent study in the World Journal of Gastrointestinal Oncology identifies charged multivesicular body protein 7 (CHMP7) as a key prognostic factor in CRC. The study showed that CHMP7 expression is significantly lower in patients with CRC with metastasis and in highly metastatic cell lines, correlating with clinical factors like normal tissue, metastatic tumors, pathologic stage, and lymphatic invasion. Higher CHMP7 expression was linked to improved overall survival, highlighting its potential as a predictive biomarker. Gene Set Enrichment Analysis also suggests the role of CHMP7 in metastasis-related pathways, paving the way for further mechanistic studies. This finding challenges current CRC management strategies and calls for larger, prospective studies to validate the role of CHMP7. As a potential target for novel diagnostics and therapies, CHMP7 could advance personalized medicine in CRC, bridging molecular insights with clinical outcomes to improve patient prognosis.

Key Words: Colorectal cancer; Charged multivesicular body protein 7; Metastasis; Prognostic biomarker; Wnt signaling; Tumor microenvironment; Micronuclear collapse

Core Tip: The downregulation of charged multivesicular body protein 7 in colorectal cancer (CRC) is linked to metastasis and poor prognosis, with roles in micronuclear collapse, organelle membrane contact sites, genomic stability, Wnt signaling, and tumor microenvironment modulation. Its prognostic significance across cancers highlights its potential for targeted CRC therapies.

INTRODUCTION

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with metastasis reducing the 5-year survival rate to below 5% in advanced cases[1,2]. Charged multivesicular body protein 7 (CHMP7), a subunit of the endosomal sorting complex required for transport III (ESCRT-III), has recently gained attention as a potential prognostic biomarker across various cancers, including CRC. Below, I explore CHMP7’s biological roles, its significance in other cancer types, and its specific implications in CRC, emphasizing the contributions of a recent study by Wei et al[3].

BIOLOGICAL ROLES OF CHMP7

CHMP7’s biological functions are deeply rooted in its role within the ESCRT-III complex, which is critical for membrane remodeling processes. It facilitates the formation of intraluminal vesicles for the degradation of ubiquitinated proteins, such as the epidermal growth factor receptor, thereby regulating autophagy and membrane repair[4,5]. Additionally, CHMP7 contributes to extracellular vesicle sorting, which influences intercellular communication by mediating the release of signaling molecules[6,7]. Stephens et al[8] further highlighted CHMP7’s role at organelle membrane contact sites (MCSs), where it localizes to regulate lipid and ion exchange between organelles like the endoplasmic reticulum and mitochondria, supporting cellular homeostasis. A pivotal aspect of CHMP7’s biology is its involvement in micronuclear collapse due to oxidative damage, as elucidated by Di Bona et al[9]. They demonstrated that mitochondria-derived reactive oxygen species (ROS) disrupt micronuclear integrity by promoting a noncanonical function of CHMP7. Specifically, ROS inhibit CHMP7 export from micronuclei, leading to its accumulation and aberrant binding to the nuclear membrane protein (LEM domain nuclear envelope protein 2) via ROS-induced cysteine oxidation. This interaction causes micronuclear envelope deformation and collapse, exposing chromatin to the cytosol and triggering chromosomal rearrangements like chromothripsis, a hallmark of aggressive cancers[9]. These diverse roles position CHMP7 as a key regulator of cellular stability and a potential contributor to cancer progression.

CHMP7’S PROGNOSTIC SIGNIFICANCE IN OTHER CANCERS

CHMP7’s relevance extends beyond CRC, with studies indicating its prognostic value across various cancer types. Table 1 summarizes its impact, drawing from references cited by Guo et al[10], Chandrashekar et al[11], Györffy et al[12], Okayama et al[13], Li et al[14], and Tyner et al[15]. In colon adenocarcinoma CRC, Chandrashekar et al[11] found that low CHMP7 expression is associated with poorer overall survival (OS) and advanced tumor stages, highlighting its tumor-suppressive role. Similarly, in breast cancer, Györffy et al[12] reported that downregulated CHMP7 expression correlates with worse OS, suggesting its potential as a biomarker for aggressive disease. Conversely, in lung adenocarcinoma, Okayama et al[13] observed that high CHMP7 expression is linked to better prognosis, indicating context-dependent roles in cancer progression. In kidney renal clear cell carcinoma, Li et al[14] noted that low CHMP7 expression predicts poor survival, reinforcing its prognostic utility. However, in acute myeloid leukemia, Tyner et al[15] found that upregulated CHMP7 expression is associated with worse prognosis, underscoring the complexity of CHMP7’s function across different malignancies. Di Bona et al[9] further demonstrated CHMP7’s role in chromothripsis across multiple cancers, linking its dysfunction to aggressive tumor behavior through micronuclear collapse and chromosomal instability.

Table 1 Prognostic significance of charged multivesicular body protein 7 in various cancers.

Cancer type	Expression pattern	Prognostic impact	Ref.
Colorectal cancer	Downregulated	Low expression linked to poorer OS, advanced stages	Chandrashekar et al[11]
Breast cancer	Downregulated	Low expression associated with worse OS	Györffy et al[12]
Lung adenocarcinoma	Upregulated	High expression correlates with better prognosis	Okayama et al[13]
Kidney renal clear cell carcinoma	Downregulated	Low expression predicts poor survival	Li et al[14]
Acute myeloid leukemia	Upregulated	High expression linked to worse prognosis	Tyner et al[15]

OS: Overall survival.

CHMP7’S ROLE IN CRC

In CRC, CHMP7’s downregulation has been consistently linked to metastasis and poor prognosis. Guo et al[10] reported reduced CHMP7 expression in CRC tissues, associating it with advanced tumor stages and poorer OS through immunohistochemical analysis of 50 patient samples. CHMP7 regulates CRC metastasis through mechanisms such as epithelial-to-mesenchymal transition and canonical Wnt signaling. Guo et al[10] used Gene Set Enrichment Analysis to demonstrate a negative correlation between CHMP7 expression and Wnt pathway activation, suggesting that CHMP7 inhibits tumor invasiveness. Low CHMP7 expression also correlates with advanced N-stage and TNM-stage, underscoring its prognostic relevance[10]. Within the tumor microenvironment (TME), CHMP7 influences immune dynamics by modulating immune cell infiltration. CHMP7 downregulation is associated with increased M2 macrophage infiltration and reduced cytotoxic T lymphocyte activity, fostering an immunosuppressive environment that promotes tumor progression[10]. Di Bona et al[9] added that micronuclear collapse, driven by CHMP7 dysfunction, triggers inflammation by exposing DNA to the cytosol, activating pathways that reshape the TME and enhance metastatic potential. Therapeutically, CHMP7 expression serves as a predictor of treatment outcomes in CRC. Lower CHMP7 expression is linked to resistance to chemotherapy drugs like oxaliplatin and paclitaxel, while higher expression indicates sensitivity, positioning CHMP7 as a potential biomarker for personalized treatment strategies[10]. Additionally, CHMP7’s dysfunction is tied to tumor hypoxia, a hallmark of CRC. Di Bona et al[9] linked ROS-induced micronuclear rupture in hypoxic regions of head and neck and ovarian tumors to CHMP7, suggesting a similar mechanism may contribute to CRC progression.

The recent study by Wei et al[3] provides critical insights into CHMP7’s role in CRC metastasis, building on the foundational understanding of its biological and prognostic significance. Using weighted gene co-expression network analysis on the GSE29621 dataset, Wei et al[3] identified significant CHMP7 downregulation in metastatic CRC tissues and cell lines (e.g., HCT116, SW620) compared to non-metastatic counterparts. Their findings correlate reduced CHMP7 expression with advanced pathologic stage, lymphatic invasion, and decreased survival (P < 0.05), reinforcing its role as a prognostic biomarker in CRC[3]. Importantly, Wei et al[3] complement Guo et al[10] by providing a comprehensive analysis of CHMP7’s association with metastatic features, offering a clearer picture of its clinical relevance. Their study strengthens the case for CHMP7 as a potential target for therapeutic intervention in CRC, particularly in metastatic cases where prognosis is poor. By linking CHMP7 downregulation to specific metastatic phenotypes, Wei et al[3] pave the way for future research into targeted therapies that could modulate CHMP7 expression to improve patient outcomes.

CONCLUSION

Future researches validate CHMP7’s prognostic role in larger CRC cohorts, comparing metastatic and non-metastatic tissues across diverse populations[16-18]. Mechanistic studies using CRISPR-based models could elucidate CHMP7’s interactions with Wnt signaling, its role at MCSs, and its involvement in micronuclear collapse, potentially identifying novel therapeutic targets[19-21]. Di Bona et al[9] suggest targeting ROS-CHMP7 interactions to mitigate micronuclear rupture, which could be explored in CRC to reduce chromosomal rearrangements and inflammation. Clinical trials evaluating CHMP7 as a predictor for immune checkpoint inhibitors and chemotherapy regimens could enhance personalized treatment strategies. Additionally, investigating CHMP7’s epigenetic regulation, alternative splicing[10], and MCS functions may uncover new regulatory mechanisms in CRC progression, advancing precision oncology.