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Lin28b is sufficient to drive liver cancer and necessary for its maintenance in murine models.

ABSTRACT: Lin28a/b are RNA-binding proteins that influence stem cell maintenance, metabolism, and oncogenesis. Poorly differentiated, aggressive cancers often overexpress Lin28, but its role in tumor initiation or maintenance has not been definitively addressed. We report that LIN28B overexpression is sufficient to initiate hepatoblastoma and hepatocellular carcinoma in murine models. We also detected Lin28b overexpression in MYC-driven hepatoblastomas, and liver-specific deletion of Lin28a/b reduced tumor burden, extended latency, and prolonged survival. Both intravenous siRNA against Lin28b and conditional Lin28b deletion reduced tumor burden and prolonged survival. Igf2bp proteins are upregulated, and Igf2bp3 is required in the context of LIN28B overexpression to promote growth. Therefore, multiple murine models demonstrate that Lin28b is both sufficient to initiate liver cancer and necessary for its maintenance.

SUBMITTER: Nguyen LH

PROVIDER: S-EPMC4145706 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Lin28b is sufficient to drive liver cancer and necessary for its maintenance in murine models.

Nguyen Liem H LH Robinton Daisy A DA Seligson Marc T MT Wu Linwei L Li Lin L Rakheja Dinesh D Comerford Sarah A SA Ramezani Saleh S Sun Xiankai X Parikh Monisha S MS Yang Erin H EH Powers John T JT Shinoda Gen G Shah Samar P SP Hammer Robert E RE Daley George Q GQ Zhu Hao H

Cancer cell 20140801 2

Lin28a/b are RNA-binding proteins that influence stem cell maintenance, metabolism, and oncogenesis. Poorly differentiated, aggressive cancers often overexpress Lin28, but its role in tumor initiation or maintenance has not been definitively addressed. We report that LIN28B overexpression is sufficient to initiate hepatoblastoma and hepatocellular carcinoma in murine models. We also detected Lin28b overexpression in MYC-driven hepatoblastomas, and liver-specific deletion of Lin28a/b reduced tumo ...[more]

PMID: 25117712

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Project description:Background New treatment options for ovarian cancer are urgently required. Tumor-associated macrophages (TAMs) are an attractive target for therapy; repolarizing TAMs from M2 (pro-tumor) to M1 (anti-tumor) phenotypes represents an important therapeutic goal. We have previously shown that upregulated NF-kappaB (NF-?B) signaling in macrophages promotes M1 polarization, but effects in the context of ovarian cancer are unknown. Therefore, we aimed to investigate the therapeutic potential of increasing macrophage NF-?B activity in immunocompetent mouse models of ovarian cancer. Methods We have generated a transgenic mouse model, termed IKFM, which allows doxycycline-inducible overexpression of a constitutively active form of IKK2 (cIKK2) specifically within macrophages. The IKFM model was used to evaluate effects of increasing macrophage NF-?B activity in syngeneic murine TBR5 and ID8-Luc models of ovarian cancer in two temporal windows: 1) in established tumors, and 2) during tumor implantation and early tumor growth. Tumor weight, ascites volume, ascites supernatant and cells, and solid tumor were collected at sacrifice. Populations of macrophages and T cells within solid tumor and/or ascites were analyzed by immunofluorescent staining and qPCR, and soluble factors in ascitic fluid were analyzed by ELISA. Comparisons of control versus IKFM groups were performed by 2-tailed Mann-Whitney test, and a P-value <?0.05 was considered statistically significant. Results Increased expression of the cIKK2 transgene in TAMs from IKFM mice was confirmed at the mRNA and protein levels. Tumors from IKFM mice, regardless of the timing of doxycycline (dox) administration, demonstrated greater necrosis and immune infiltration than control tumors. Analysis of IKFM ascites and tumors showed sustained shifts in macrophage populations away from the M2 and towards the anti-tumor M1 phenotype. There were also increased tumor-infiltrating CD3+/CD8+ T cells in IKFM mice, accompanied by higher levels of CXCL9, a T cell activating factor secreted by macrophages, in IKFM ascitic fluid. Conclusions In syngeneic ovarian cancer models, increased canonical NF-?B signaling in macrophages promoted anti-tumor TAM phenotypes and increased cytotoxic T cell infiltration, which was sufficient to limit tumor progression. This may present a novel translational approach for ovarian cancer treatment, with the potential to increase responses to T cell-directed therapy in future studies.

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Lin28b is sufficient to drive liver cancer and necessary for its maintenance in murine models.

Publications

Lin28b is sufficient to drive liver cancer and necessary for its maintenance in murine models.

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