Siglec15 Activates the PI3K/AKT Signaling Pathway and Promotes Malignant Progression of Hepatocellular Carcinoma

doi:10.3870/j.issn.1672-8009.2026.05.005

Abstract

Abstract: Objective To investigate the role of sialic acid-bound immunoglobulin-like lectin 15 （Siglec15） in the occurrence and development of hepatocellular carcinoma （HCC） and its underlying mechanism. Methods Online databases were utilized to analyze the expression pattern of Siglec15 in HCC, followed by validation in HCC cell lines. HCC cell models with Siglec15 overexpression or knockdown were established to evaluate the regulatory effects of Siglec15 on the proliferation and migration of HCC cells. A subcutaneous tumor xenograft model in nude mice was constructed to observe the impact of Siglec15 overexpression on tumor growth in vivo. Transcriptome sequencing combined with KEGG pathway enrichment analysis was performed, and the related signaling pathways were further verified by qRT-PCR and Western blotting. Moreover, the expression levels of key molecules in the PI3K/AKT signaling pathway （p-PI3K, p-AKT） as well as proteins associated with cell cycle regulation and apoptosis （P53, Caspase3, Bax, Bcl-2） were detected. Results Compared with that in the adjacent normal liver tissues, Siglec15 was significantly upregulated both in the HCC tissues and cell lines （P<0.05）. Knockdown of Siglec15 markedly suppressed the proliferation and migration capacities of the HCC cell line SMMC-7721 （P<0.05）. The nude mouse xenograft experiment demonstrated that Siglec15 overexpression promoted tumor growth in vivo. Transcriptome sequencing identified 4 765 differentially expressed genes, among which the expression alterations of core moleculars involved in the PI3K-AKT pathway （PI3K, AKT, Bcl-2, CCNA2, P53, etc.） were highly consistent with the observed cellular phenotypes. Validation experiments confirmed that Siglec15 overexpression upregulated the mRNA expression of PI3K, AKT, Bcl-2 and CCNA2 while downregulating that of P53, Caspase3 and Bax. Meanwhile, Siglec15 overexpression significantly increased the phosphorylation levels of PI3K and AKT proteins, with concomitant modulation of the expression of downstream apoptosis and cell cycle-related proteins. Conversely, the Siglec15 knockdown group exhibited the opposite trends. Conclusion Siglec15 promotes the proliferation and migration of HCC cells by activating the PI3K/AKT signaling pathway, primarily via post-translational phosphorylation modification, which in turn regulates the expression of downstream apoptosis- and cell cycle-associated proteins. Therefore, Siglec15 may serve as a potential therapeutic target for HCC.

Key words: hepatocellular carcinoma, sialic acid-bound immunoglobulin-like lectin 15, proliferation, PI3K/AKT signaling pathway

CLC Number:

R735.7

NIU Yujie, MA Xiangyu, LIN Wen, GUAN Lulu, GUO Cairu. Siglec15 Activates the PI3K/AKT Signaling Pathway and Promotes Malignant Progression of Hepatocellular Carcinoma[J]. Journal of Medical Molecular Biology, 2026, 23(5): 514-522.

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