Page 264 - EJMO-9-3

Eurasian Journal of
Medicine and Oncology Metastasis gene expression in colorectal cancer

The roles of SNAI1, ZEB1, Slug, Twist, and TNF-α the importance of microenvironmental inflammation in
in colon cancer progression reveal complex interactions colon cancer progression. Therefore, TNF-α has a dual
between EMT-related transcription factors and role in both inflammation and EMT, with both showing
inflammatory signaling, as shown in recent studies. a similar expression pattern in the liver metastasis group.
Overexpression of SNAI1 induces partial or complete EMT In addition, the observed downregulation of MTA3 in
in colon cancer cells, correlating with chemoresistance, metastatic cases suggests a tumor-suppressive function.
reduced apoptosis, and increased tumor growth. 42,43 Restoring MTA3 activity could thus represent another
Mechanistically, TNF-α stabilizes SNAI1 protein through avenue for therapeutic intervention. Epigenetic drugs that
the AKT/GSK-3β signaling, bypassing transcriptional modulate MTA3 expression or activity warrant further
upregulation. In addition, phosphorylation of sirtuin 1 at investigation in preclinical CRC models. While MTA3
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Ser27 further stabilizes SNAI1, enhancing its deacetylase has not been directly addressed in the recent studies, its
activity and promoting interleukin-6 and interleukin-8- known role in repressing SNAI1 in breast cancer suggests a
mediated tumor progression. These findings position potential cross-talk in colon cancer. Future studies should
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SNAI1 as a critical node in EMT regulation, with its explore whether MTA3 loss contributes to SNAI1 activation
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expression levels dictating phenotypic outcomes. As in colorectal tumors. In this study, MTA3 expression was
shown in Figure 1, SNAI1 expression is highest in the liver found to be decreased in the liver metastasis group and
metastasis group. This indicates the role of SNAI1 as a elevated in the non-metastasis group (Table 1), supporting
central driver of EMT and chemoresistance. its proposed role as a metastasis suppressor.
The context-dependent roles of ZEB1 and Slug in The correlation of SNAI1, ZEB1, Slug, Twist, and
colon cancer, as revealed in this study, also underscore TNF-α with BMI and AST in cancer involves their roles
the necessity for patient stratification in future therapeutic in EMT, cancer progression, and inflammation, though
interventions. Since ZEB1 and Slug expression is elevated direct correlations with BMI and AST specifically are not
in liver metastatic lesions, their detection could serve as extensively detailed in the provided sources. However,
biomarkers of aggressive disease and guide the application based on the results of this study, these markers were found
of more intensive or targeted therapeutic regimens. to correlate with BMI and AST (Table 3). The decrease
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Liquid biopsy approaches, such as the measurement of in BMI, as shown in Table 2, indicates the occurrence of
circulating tumor cells or cell-free nucleic acids expressing cachexia in the subjects studied. Cachexia in colon cancer
these EMT-transcription factors (EMT-TFs), may provide involves complex interactions between transcription
non-invasive means for real-time disease monitoring and factors and inflammatory mediators, with SNAI1, ZEB1,
early detection of metastasis. Although ZEB1 and Slug Twist1, and TNF-α playing significant roles. 55-57 Cachexia
contribute to EMT in other cancers, their involvements in progression in colon cancer involves energy metabolism
colon cancer appear context-dependent. 48,49 For instance, disruption (e.g., impaired amino acid metabolism)
TNF-α induces Slug in papillary thyroid cancer, while in and elevated serum lysine/acetate, which may serve
colon cancer, SNAI1 predominates in regulating EMT. as diagnostic biomarkers. EMT-related transcription
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Some herbal or natural bioactive compounds have been factors (ZEB1, Twist1, and SNAI1) contribute to tumor
shown to suppress SNAI1 through NF-κB inhibition, resilience and metastasis, indirectly perpetuating cachexia
highlighting SNAI1’s primacy over other EMT-TFs in by sustaining tumor-derived catabolic signals (e.g., activin
therapeutic targeting. 50,51 As in Figure 1, it is clear that A). 55-57 ZEB1, Twist1, and SNAI1 drive tumor progression
ZEB1 and Slug expression increase in the liver metastasis and cachexia in colon cancer through EMT, anti-apoptotic
group. signaling, and muscle degradation pathways, while TNF-α
Although less studied in colon cancer, Twist has and systemic inflammation amplify these effects.
also been implicated in contributing to metastasis by According to another study, TNF-α also showed a
promoting cancer stem cell-like traits. Another study direct, concentration-dependent correlation with AST.
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found that Manuka honey downregulates Twist, Slug, and The relationship of AST was not directly correlated with
SNAI1 in colonospheres, thereby reducing migration and SNAI1, ZEB1, Slug, and Twist, but these markers contribute
angiogenesis. This suggests that combinatorial targeting to the development of cancer and liver-related pathologies,
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of EMT-TFs could enhance therapeutic efficacy. TNF-α potentially increasing AST through metastasis, immune
also orchestrates a pro-metastatic niche by stabilizing infiltration, or hepatocyte damage. The prognostic value
SNAI1 and activating stromal fibroblasts expressing SNAI1, of an increased AST ratio independently predicted the
which, in turn, enhances cancer cell proliferation and risk and mortality of cancer, which underlines the need to
invasion. 21,53 This stromal-epithelial crosstalk underscores monitor liver function in cancer patients. This is in line
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Volume 9 Issue 3 (2025) 256 doi: 10.36922/EJMO025210202