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LAPTM4B-YAP loop feedback amplification enhances the stemness of hepatocellular carcinoma.

ABSTRACT: Hepatocellular carcinoma (HCC) is highly heterogeneous, and stemness signatures are frequently elevated in HCC tumor cells to generate heterogeneous subtypes via multidirectional differentiation. However, the mechanisms affecting the regulation of stemness in HCC remain unclear. In this study, we identified that lysosome-associated protein transmembrane-4β (LAPTM4B) was significantly overexpressed in stem-like tumor cell populations with multidirectional differentiation potential at the single cell level, and verified that LAPTM4B was closely related to stemness of HCC using in vitro and in vivo experiments. Mechanistically, elevated LAPTM4B suppresses Yes-associated protein (YAP) phosphorylation and ubiquitination degradation. In turn, stabilized YAP localizes to the nucleus and binds to cAMP responsive element binding protein-1 (CREB1), which promotes transcription of LAPTM4B. Overall, our findings suggest that LAPTM4B forms a positive feedback loop with YAP, which maintains the stemness of HCC tumor cells and leads to an unfavorable prognosis for HCC patients.

SUBMITTER: Liao J

PROVIDER: S-EPMC10197148 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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LAPTM4B-YAP loop feedback amplification enhances the stemness of hepatocellular carcinoma.

Liao Jianping J Wang Jiahong J Xu Yu Y Wu Yong Y Wang Meifeng M Zhao Qiudong Q Tan Xiaodan X Meng Yan Y Wei Lixin L Huang Aimin A

iScience 20230427 6

Hepatocellular carcinoma (HCC) is highly heterogeneous, and stemness signatures are frequently elevated in HCC tumor cells to generate heterogeneous subtypes via multidirectional differentiation. However, the mechanisms affecting the regulation of stemness in HCC remain unclear. In this study, we identified that lysosome-associated protein transmembrane-4β (LAPTM4B) was significantly overexpressed in stem-like tumor cell populations with multidirectional differentiation potential at the single c ...[more]

PMID: 37213231

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Project description:BackgroundLiver cancer stem cells (LCSCs) play key roles in the metastasis, recurrence, and chemotherapeutic resistance of hepatocellular carcinoma (HCC). Our previous research showed that the POSTN gene is closely related to the malignant progression and poor prognosis of HCC. This study aimed to elucidate the role of POSTN in generating LCSCs and maintaining their stemness as well as the underlying mechanisms.MethodsHuman HCC tissues and matched adjacent normal tissues were obtained from 110 patients. Immunohistochemistry, western blotting (WB), and RT-PCR were performed to detect the expression of POSTN and stemness factors. The roles of transforming growth factor (TGF)-β1 and AP-2α in the POSTN-induced stemness transformation of HCC cells were explored in vitro and in vivo using LCSCs obtained by CD133+ cell sorting.ResultsThe high expression of POSTN was correlated with the expression of various stemness factors, particularly CD133, in our HCC patient cohort and in TCGA and ICGC datasets. Knockdown of POSTN expression decreased the abilities of HCC cell lines to form tumours in xenograft mouse models. Knockdown of POSTN expression also suppressed cell viability and clone formation, invasion, and sphere formation abilities in vitro. Knockdown of AP-2α attenuated the generation of CD133+ LCSCs and their malignant behaviours, indicating that AP-2α was a critical factor that mediated the POSTN-induced stemness transformation and maintenance of HCC cells. The role of AP-2α was verified by using a specific αvβ3 antagonist, cilengitide, in vitro and in vivo. Activation of POSTN could release TGFβ1 from the extracellular matrix and initiated POSTN/TGFβ1 positive feedback signalling. Furthermore, we found that the combined use of cilengitide and lenvatinib suppressed the growth of HCC cells with high POSTN expression more effectively than the use of lenvatinib alone in the patient-derived xenograft (PDX) mouse model.ConclusionsThe POSTN/TGFβ1 positive feedback pathway regulates the expression of stemness factors and the malignant progression of HCC cells by regulating the transcriptional activation of AP-2α. This pathway may serve as a new target for targeted gene therapy in HCC.

Project description:BackgroundEmerging evidence indicates that circular RNAs (circRNAs) and m6A RNA methylation participate in the pathogenesis and metastasis of multiple malignancies including hepatocellular carcinoma (HCC). However, it remains undocumented how circRNAs form a feedback loop with the m6A modification contributing to HCC.MethodsA novel hsa_circ_0017114 (circGPR137B) was identified from three pairs of primary HCC and adjacent normal tissues by circRNA expression profiling. The association of circGPR137B and miR-4739 with clinicopathological parameters and prognosis in patients with HCC was analyzed by RT-qPCR, fluorescence in situ hybridization and TCGA cohorts. The role of circGPR137B in HCC was estimated in vitro and in vivo. RT-qPCR, western blot, m6A dot blot, RIP, MeRIP and dual-luciferase reporter assays were used to validate the reciprocal regulation of the feedback loop among circGPR137B, miR-4739 and m6A demethylase FTO. Meanwhile, the expression, function and prognosis of FTO in HCC were investigated by RT-qPCR, western blot, TCGA and rescue experiments.ResultsWe identified a new dramatically downregulated circGPR137B in HCC tissues, and found that downregulation of circGPR137B or upregulation of miR-4739 was associated with poor prognosis in patients with HCC. Ectopic expression of circGPR137B strikingly repressed the proliferation, colony formation and invasion, whereas knockdown of circGPR137B harbored the opposite effects. Moreover, restored expression of circGPR137B inhibited tumor growth and lung metastasis in vivo. Further investigations showed that circGPR137B, co-localized with miR-4739 in the cytoplasm, acted as a sponge for miR-4739 to upregulate its target FTO, which mediated m6A demethylation of circGPR137B and promoted its expression. Thus, a feedback loop comprising circGPR137B/miR-4739/FTO axis was formed. FTO suppressed cell growth and indicated favorable survival in patients with HCC.ConclusionOur results demonstrate that circGPR137B inhibits HCC tumorigenesis and metastasis through the circGPR137B/miR-4739/FTO feedback loop. This positive feedback mechanism executed by functional coupling between a circRNA sponge and an m6A modification event suggests a model for epigenetics.

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LAPTM4B-YAP loop feedback amplification enhances the stemness of hepatocellular carcinoma.

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LAPTM4B-YAP loop feedback amplification enhances the stemness of hepatocellular carcinoma.

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