KIF23 regulation by miR-107 controls replicative tumor cell fitness in mouse and human hepatocellular carcinoma

Castoldi, M.; Roy, S.; Lohr, C.; Pellegrino, R.; Vucur, M.; Singer, M. T.; Buettner, V.; Dille, M. A.; Heij, L. R.; Zender, L.; Neumann, U. P.; Longerich, T.; Roderburg, C.; Luedde, T.

doi:10.1101/2023.11.20.565448

bioRxiv · 10.1101/2023.11.20.565448

KIF23 regulation by miR-107 controls replicative tumor cell fitness in mouse and human hepatocellular carcinoma

Castoldi, M.·Roy, S.·Lohr, C.·Pellegrino, R.·Vucur, M.·Singer, M. T.·Buettner, V.·Dille, M. A.·Heij, L. R.·Zender, L.·Neumann, U. P.·Longerich, T.·Roderburg, C.·Luedde, T.

View original source ↗Export metadata ↓

Abstract

Background & AimsIn hepatocellular carcinoma, there is a lack of successful translation of experimental targets identified in mouse models to human patients. In this study, we used a comprehensive transcriptomic approach in mice to identify novel potential targets for therapeutic intervention in humans. MethodsWe analysed combined genome-wide miRNA and mRNA expression data in three pathogenically distinct mouse models of liver cancer. Effects of target genes on hepatoma cell fitness were evaluated by proliferation, survival and motility assays. TCGA and GEO databases, in combination with tissue microarrays (TMA), were used to validate the mouse targets and their impact on human HCC prognosis. Finally, the functional effects of the identified targets on tumorigenesis and tumor therapy were tested in hydrodynamic tail vein injection (HDTVi)-based preclinical HCC models in vivo. ResultsThe expression of miR-107 was found to be significantly reduced in mouse models of liver tumors of various etiologies and in cohorts of human HCC patients. Overexpression of miR-107 or inhibition of its novel target Kinesin family member 23 (Kif23) significantly reduced proliferation by interfering with cytokinesis, thereby controlling survival and motility of mouse and human hepatoma cells. In humans, KIF23 expression was found to be a prognostic marker in liver cancer, with high expression associated with poor prognosis. HDTVi of vectors carrying either pre-miR- 107 or anti-Kif23 shRNA inhibited the development of highly aggressive cMyc-NRas- induced liver cancers in mice. ConclusionsDisruption of the miR-107/Kif23 axis inhibited hepatoma cell proliferation in vitro and prevented oncogene-induced liver cancer development in vivo, offering a novel potential avenue for the treatment of HCC in humans. Impact and implicationsA comprehensive analysis integrating in silico prediction, miRNA and mRNA data in three pathogenically distinct mouse models provided novel targets for the treatment of human HCC, bridging the translational gap between mouse data and human HCC. Our functional findings on the novel miR-107/Kif23 module provide important new insights into the control of mitosis in liver cancer cells. The findings that miR-107 overexpression or Kif23 inhibition had a dramatic functional effect on inhibiting the growth of liver cancer cells in vitro and in vivo suggest that the miR-107/Kif23 axis may be a promising novel target and potential adjunct to sequential systemic therapy of HCC. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=164 SRC="FIGDIR/small/565448v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@afda02org.highwire.dtl.DTLVardef@111da7borg.highwire.dtl.DTLVardef@11eeeecorg.highwire.dtl.DTLVardef@1d7d9f7_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LImiR-107 is globally downregulated in mouse liver cancers of different etiologies and represents a potential biomarker in human HCC. C_LIO_LIIntegration of in-silico-prediction, miRNA and mRNA transcriptomics identified KIF23, a mitotic spindle-associated protein, as a specific target mediating the biological effects of miR-107. C_LIO_LIThe miR-107/KIF23 module promotes replicative fitness of liver cancer cells through an essential function in cytokinesis C_LIO_LIMice receiving shRNA targeting Kif23 were completely protected from oncogene-induced liver cancer. C_LI

Source connections

Published article ↗

Explore related subjects

cancer biology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Castoldi, M., Roy, S., Lohr, C., Pellegrino, R., Vucur, M., Singer, M. T., Buettner, V., Dille, M. A., Heij, L. R., Zender, L., Neumann, U. P., Longerich, T., Roderburg, C., Luedde, T.. 2023-11-20. KIF23 regulation by miR-107 controls replicative tumor cell fitness in mouse and human hepatocellular carcinoma. https://doi.org/10.1101/2023.11.20.565448

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Tet2-Clonal Hematopoiesis Promotes Whereas Dnmt3a-CH Inhibits Breast Cancer Progression During Aging

Clonal hematopoiesis of indeterminate potential (CHIP) driven by somatic mutations in blood cells increases with age and is associated with adverse outcomes in cancer patients. How CHIP mutations influence solid tumor progression remains unclear. Using inducible murine models of Dnmt3a- or Tet2-mutant CHIP combined with orthotopic syngeneic breast cancer models, we demonstrate that upon aging Dnmt3a-mutant CHIP prevents whereas Tet2-mutant CHIP drives breast cancer progression. Dnmt3a-mutant immune infiltrates established interferon-mediated MHCIIhigh tumor-associated macrophages (TAMs) that supported cytotoxic CD8+ T cell-mediated tumor rejection. In contrast, Tet2-mutant TAMs exhibited an inflammatory, immunosuppressive phenotype characterized by increased IL-1 and CXCL2 production, reduced MHCII expression, and impaired T cell recruitment and activation. Therapeutic blockade of IL-1R1 or CXCR2 reduced tumor progression in aged Tet2-mutant CHIP mice and partially restored anti-tumor immunity. These findings establish that the effects of CHIP on cancer are mutation- and age-dependent and identify IL-1/CXCL2-driven inflammation as a therapeutic vulnerability of tumor-promoting Tet2-mutant CHIP.

cancer biology↗

bioRxiv2026

Single Nucleus Profiling Reveals Rewired Tumor-Immune-Stromal Cell Communication in Plasmacytoid Urothelial Carcinoma

Plasmacytoid urothelial carcinoma (PUC) is an aggressive histologic subtype of bladder cancer associated with worse patient outcomes and therapeutic response compared to conventional urothelial carcinoma (CUC). While recent work has demonstrated metastatic lymph nodes from PUC tumors have an inflamed phenotype, how the tumor microenvironment (TME) and crosstalk between tumor, stromal, and immune cells in primary PUC bladder tumors differs from those in CUC remains poorly understood. The impact of these differences on response to immunotherapy is also unknown. To understand TME differences between CUC and PUC and their impact on cell signaling, we performed single nucleus RNA sequencing on PUC and CUC tumors, as well as Xenium spatial transcriptomics on a mixed CUC / PUC tumor. We identified increased signaling between PUC-enriched, CDH1-low urothelial cells, immunosuppressive lipid-associated macrophages, and SFRP2+/CTHRC1+ fibroblasts in PUC tumors compared to CUC. Spatial transcriptomics identified increased macrophage infiltration in PUC histology and colocalization of PUC tumor cells, immunosuppressive macrophages, and SFRP2+ fibroblasts. Taken together, this study delineates PUC architecture and demonstrates interplay CDH1-low tumor cells, EMT, and immunosuppressive macrophages, identifying possible therapeutic vulnerabilities in PUC.

cancer biology↗

bioRxiv2026

The Phospholipase A2 Activity of Peroxiredoxin 6 Protects Hepatocarcinoma Cells Against Ferroptosis and Mitophagy Impairment

Peroxiredoxin 6 (PRDX6) is a moonlighting protein that plays a key role in regulating redox homeostasis and lipid metabolism through its unique dual peroxidase and calcium-independent phospholipase A2 (iPLA2) activities. Here, we generated a stable HepG2 cell line harboring a D140A mutation to selectively ablate iPLA2 activity, and we compared its phenotype with that of wild-type (WT) and PRDX6-knockout (KO) cells. D140A exhibited low ROS leves, similar to WT cells, confirming that oxidative stress is due to peroxidase deficiency. In contrast, D140A cells displayed higher lipid peroxidation than WT cells, though significantly lower than that of KO cells. Furthermore, the D140A mutant mirrored the KO phenotype regarding intracellular ferrous iron accumulation, impaired lipid droplet biogenesis, and the downregulation of the key ferroptosis regulator GPX4. Mechanistically, integrated proteomic, lipidomic, and enzymatic analyses revealed that a deficiency in iPLA2 activity of PRDX6 disrupted the release of key lipid species necessary for cell structure and signaling. Consequently, organelles involved in lipid synthesis and trafficking, such as peroxisomes, endoplasmic reticulum, mitochondria and lipid droplet, were affected. Specifically, we found that mitochondria exhibited a reduction in cristae and a diminished capacity for mitophagy and autophagy, which ultimately makes cells much more susceptible to erastin-induced ferroptotic cell death. Taken together, our findings demonstrate that PRDX6 iPLA2 activity uniquely coordinates organelle lipid homeostasis and mitophagy to protect cancer cells from ferroptotic cell death. Consequently, the use of iPLA2 inhibitors such as MJ33, which decreased PRDX6 iPLA2 activity to a level comparable to the mutant D140A, could represent a promising therapeutic strategy for inducing ferroptotic cell death in hepatocellular carcinoma.

cancer biology↗