Cell Commun Signal. 2026 Sep 11;24(1):488. doi: 10.1186/s12964-026-03206-2.

ABSTRACT

BACKGROUND: While over 170 RNA modifications have been identified and implicated in various cancers, their role in hepatocellular carcinoma (HCC) progression is increasingly recognized. Despite this established relevance in tumor biology, the landscape of RNA modifications in the peripheral blood of HCC patients-and their potential diagnostic utility-remains largely unexplored.

METHODS: Peripheral blood samples from patients with HCC, liver cirrhosis (LC), and normal healthy (NH) controls were collected. The abundances of 55 RNA modifications were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to assess their diagnostic potential for HCC, particularly at early stages. Correlations among these modifications and their associations with clinical parameters were analyzed. Simultaneously, differentially expressed genes, including those encoding RNA-modifying enzymes, were screened in peripheral blood. The biological relevance of the identified signatures was subsequently validated using in vitro co-culture and in vivo syngeneic HCC mouse models.

RESULTS: Compared to the combined non-HCC group (NH and LC), the abundances of 11 RNA modifications were significantly altered in both overall and stage I HCC groups, with N²,N²-dimethylguanosine (m^2,2G) emerging as a key component exhibiting the most pronounced dysregulation. A diagnostic model centered on an m^2,2G-based modification panel achieved area under the curves (AUCs) of 0.901 and 0.891 for detecting HCC and stage I HCC, respectively, demonstrating promising diagnostic potential. Notably, the incorporation of two upregulated genes in peripheral blood-IFI27 and CCR2-significantly enhanced the model's performance, yielding improved AUCs of 0.972 and 0.968, respectively. Further analysis revealed distinct correlation patterns among RNA modifications, as well as between RNA modifications and clinical laboratory parameters, exhibiting both shared and HCC-specific features that suggest systemic reprogramming of RNA modification network in HCC. This biological relevance was confirmed by elevated m^2,2G abundances in human lymphocytes co-cultured with HCC cells and blood from a syngeneic HCC mouse model.

CONCLUSIONS: This study systematically profiled peripheral blood RNA modifications and provided preliminary evidence supporting their potential as diagnostic biomarkers for HCC. By integrating key modifications (m^2,2G, m^2,2,7G, m^6,6A) with two mRNA markers (IFI27 and CCR2), we developed a multi-omics signature that demonstrated promising diagnostic performance, particularly for early-stage HCC.

PMID:42732057 | PMC:PMC13570552 | DOI:10.1186/s12964-026-03206-2

Cell Commun Signal. 2026 Sep 11;24(1):488. doi: 10.1186/s12964-026-03206-2.

ABSTRACT

BACKGROUND: While over 170 RNA modifications have been identified and implicated in various cancers, their role in hepatocellular carcinoma (HCC) progression is increasingly recognized. Despite this established relevance in tumor biology, the landscape of RNA modifications in the peripheral blood of HCC patients-and their potential diagnostic utility-remains largely unexplored.

METHODS: Peripheral blood samples from patients with HCC, liver cirrhosis (LC), and normal healthy (NH) controls were collected. The abundances of 55 RNA modifications were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to assess their diagnostic potential for HCC, particularly at early stages. Correlations among these modifications and their associations with clinical parameters were analyzed. Simultaneously, differentially expressed genes, including those encoding RNA-modifying enzymes, were screened in peripheral blood. The biological relevance of the identified signatures was subsequently validated using in vitro co-culture and in vivo syngeneic HCC mouse models.

RESULTS: Compared to the combined non-HCC group (NH and LC), the abundances of 11 RNA modifications were significantly altered in both overall and stage I HCC groups, with N²,N²-dimethylguanosine (m^2,2G) emerging as a key component exhibiting the most pronounced dysregulation. A diagnostic model centered on an m^2,2G-based modification panel achieved area under the curves (AUCs) of 0.901 and 0.891 for detecting HCC and stage I HCC, respectively, demonstrating promising diagnostic potential. Notably, the incorporation of two upregulated genes in peripheral blood-IFI27 and CCR2-significantly enhanced the model's performance, yielding improved AUCs of 0.972 and 0.968, respectively. Further analysis revealed distinct correlation patterns among RNA modifications, as well as between RNA modifications and clinical laboratory parameters, exhibiting both shared and HCC-specific features that suggest systemic reprogramming of RNA modification network in HCC. This biological relevance was confirmed by elevated m^2,2G abundances in human lymphocytes co-cultured with HCC cells and blood from a syngeneic HCC mouse model.

CONCLUSIONS: This study systematically profiled peripheral blood RNA modifications and provided preliminary evidence supporting their potential as diagnostic biomarkers for HCC. By integrating key modifications (m^2,2G, m^2,2,7G, m^6,6A) with two mRNA markers (IFI27 and CCR2), we developed a multi-omics signature that demonstrated promising diagnostic performance, particularly for early-stage HCC.

PMID:42732057 | PMC:PMC13570552 | DOI:10.1186/s12964-026-03206-2

Discov Oncol. 2026 Apr 11. doi: 10.1007/s12672-026-04951-z. Online ahead of print.

ABSTRACT

BACKGROUND: Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality. Chromosome 8 open reading frame 33 (C8orf33) has been noted as a potential oncogenic factor in several cancers, but its biological roles and regulatory mechanism in HCC microenvironment remain unknown.

METHODS: We integrated bulk RNA sequencing, single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics (ST) to characterize the expression landscape of C8orf33. We then performed C8orf33 loss-of-function studies in HCC cell lines, including in vitro phenotypic assays and subcutaneous xenografts.

RESULTS: C8orf33 was broadly overexpressed and associated with unfavorable prognosis across multiple Cancers. In HCC, higher C8orf33 aligned with advanced stage and shorter overall survival. C8orf33 knockdown reduced proliferation and migration, impaired tumorigenic capacity, and increased apoptosis. ScRNA-seq analyses identified a malignant population of Epi3 with high C8orf33 expression. Cell-cell communication analysis suggested that C8orf33-high Epi3 state was associated with an enriched MIF-CD74/CXCR4/CD44 signaling program toward macrophage populations with M2-like features. ST analyses further confirmed the colocalization of C8orf33 with malignant features in tumor cores. In Huh7 cells, C8orf33 knockdown was accompanied by reduced mRNA and protein levels of MIF and its receptor components. Consistently, xenografts derived from C8orf33-silenced cells showed lower expression of these MIF-axis components and reduced infiltration of CD163 and CD206-positive macrophages.

CONCLUSION: These results support a tumor-promoting association of C8orf33 in HCC and suggest a potential link to macrophage-associated immunomodulatory features, nominating C8orf33 as a candidate biomarker and therapeutic target.

PMID:41965457 | DOI:10.1007/s12672-026-04951-z

Discov Oncol. 2026 Apr 11. doi: 10.1007/s12672-026-04951-z. Online ahead of print.

ABSTRACT

BACKGROUND: Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality. Chromosome 8 open reading frame 33 (C8orf33) has been noted as a potential oncogenic factor in several cancers, but its biological roles and regulatory mechanism in HCC microenvironment remain unknown.

METHODS: We integrated bulk RNA sequencing, single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics (ST) to characterize the expression landscape of C8orf33. We then performed C8orf33 loss-of-function studies in HCC cell lines, including in vitro phenotypic assays and subcutaneous xenografts.

RESULTS: C8orf33 was broadly overexpressed and associated with unfavorable prognosis across multiple Cancers. In HCC, higher C8orf33 aligned with advanced stage and shorter overall survival. C8orf33 knockdown reduced proliferation and migration, impaired tumorigenic capacity, and increased apoptosis. ScRNA-seq analyses identified a malignant population of Epi3 with high C8orf33 expression. Cell-cell communication analysis suggested that C8orf33-high Epi3 state was associated with an enriched MIF-CD74/CXCR4/CD44 signaling program toward macrophage populations with M2-like features. ST analyses further confirmed the colocalization of C8orf33 with malignant features in tumor cores. In Huh7 cells, C8orf33 knockdown was accompanied by reduced mRNA and protein levels of MIF and its receptor components. Consistently, xenografts derived from C8orf33-silenced cells showed lower expression of these MIF-axis components and reduced infiltration of CD163 and CD206-positive macrophages.

CONCLUSION: These results support a tumor-promoting association of C8orf33 in HCC and suggest a potential link to macrophage-associated immunomodulatory features, nominating C8orf33 as a candidate biomarker and therapeutic target.

PMID:41965457 | DOI:10.1007/s12672-026-04951-z