Comprehensive analysis of IGFL1 in colorectal cancer and its promotion of tumour progression via inhibition of lipophagy.

[OBJECTIVE] Colorectal cancer (CRC) ranks among the most prevalent malignancies, with increasing incidence and mortality rates presenting a substantial public health challenge. While insulin growth factor like family member 1 (IGFL1) has been implicated in the regulation of various diseases, its functional role in colorectal cancer remains poorly characterised. This study therefore aims to elucidate the involvement of IGFL1 in CRC through an integrated approach combining bioinformatics analysis and experimental validation.

[METHODS] The expression of IGFL1 in CRC and its association with clinicopathological features, diagnostic relevance, and patient prognosis were evaluated using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Immunohistochemistry was performed to validate IGFL1 protein expression in CRC tissue samples. Immune cell infiltration levels and immune microenvironment scores related to IGFL1 expression were analysed using multiple computational algorithms, including CIBERSORT, ssGSEA, ESTIMATE, EPIC, MCP-counter, quanTIseq, TIMER, xCell, and CIBERSOR. Furthermore, IGFL1 expression patterns across distinct cellular subpopulations were examined using single-cell RNA sequencing datasets from the Tumor Immune Single-cell Hub (TISCH) database. The TIDE algorithm was applied to assess the potential clinical efficacy of immunotherapy in groups with high versus low IGFL1 expression, in addition to investigating correlations between IGFL1 expression and immune checkpoint markers. Genetic alterations of IGFL1 were analysed via cBioPortal, while the TIMER2.0 database was used to explore relationships between IGFL1 expression and key gene mutations in CRC. The CTRP and GDSC databases were employed to investigate associations between IGFL1 expression and sensitivity to conventional chemotherapy drugs. Finally, phenotypic validation and mechanistic studies were conducted using the CRC cell lines SW620 and HCT116.

[RESULTS] Our study demonstrates that IGFL1 expression is significantly up-regulated in CRC and possesses considerable diagnostic value. Elevated IGFL1 levels were consistently observed in clinical specimens, where high expression correlated with adverse clinicopathological features, poorer prognosis, and mutations in key oncogenes. Within the tumour microenvironment, IGFL1 appears to play a critical role in modulating the infiltration of diverse immune cell populations. Furthermore, IGFL1 expression influences both immunotherapy responsiveness and chemotherapy sensitivity in CRC patients. Genetic knockdown of IGFL1 markedly attenuated the malignant phenotype of CRC cells. RNA-sequencing analysis revealed that IGFL1 is closely linked to cholesterol metabolism, autophagy pathways, and ATP hydrolysis activity. Functionally, inhibition of IGFL1 enhanced lipophagy in CRC cells. Collectively, these findings indicate that IGFL1 promotes CRC pathogenesis and progression through the suppression of lipophagy.

[CONCLUSIONS] IGFL1 exhibits oncogenic properties in colorectal cancer and may represent a potential therapeutic target.