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Tuftelin 1 Facilitates Hepatocellular Carcinoma Progression through Regulation of Lipogenesis and Focal Adhesion Maturation.

ABSTRACT: Hepatocellular carcinoma (HCC) is the most common type of primary liver malignancy with poor prognosis worldwide. Emerging evidences demonstrated critical roles of lipid de novo synthesis in HCC progression, yet its regulatory mechanisms are not fully understood. Herein, we found that tuftelin 1 (TUFT1), an acidic phosphorylated glycoprotein with secretory capacity, was significantly upregulated in HCC and had an excellent correlation with patient survival and malignancy features. Through database mining and experimental validation, we found that TUFT1 was associated with fatty acid metabolism and promoted lipid accumulation in HCC cells. Further, we found that TUFT1 can interact with CREB1, a transcription factor for hepatic lipid metabolism, and regulate its activity and the transcriptions of key enzymes for lipogenesis. TUFT1 promoted HCC cell proliferation significantly, which was partially reversed by treatment of an inhibitor of CREB1, KG-501. Moreover, TUFT1 promoted the capacity of HCC cell invasion in vitro, which was likely mediated by its association with zyxin, a zinc-binding phosphoprotein responsible for the formation of fully mature focal adhesions on extracellular matrix. We found that TUFT1 can interact with ZYX and inhibit its expression and recruitments to focal complexes in HCC cells. Collectively, our study uncovered new regulatory mechanisms of TUFT1-mediated lipogenesis, cell proliferation, and invasion.

SUBMITTER: Zhu L

PROVIDER: S-EPMC9234046 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundTumor microenvironment (TME) plays a very important role in cancer progression. The mesenchymal stem cells (MSC), a major compartment of TME, have been shown to promote hepatocellular carcinoma (HCC) progression and metastasis. As hypoxia is a common feature of TME, it is essential to investigate the effects of hypoxia on MSC during HCC progression.MethodsThe effects of hypoxia on MSC mediated cell proliferation and HCC progression were measured by cell counting kit-8 (CCK-8) assay, Edu incorporation assay and xenograft model. The role of cyclooxygenase 2 (COX2) during this process was evaluated via lentivirus mediated COX2 knockdown in MSC. We also assessed the levels and localization of yes-associated protein (YAP) in HCC cells by immunofluorescence, western blot and real-time PCR, in order to detect the alterations of Hippo pathway. The changes in lipogenesis was examined by triacylglycerol (TG) levels, BODIPY staining of neutral lipid, and lipogenic enzyme levels. The alterations in AKT/mTOR/SREBP1 pathway were measured by western blot. In addition, to evaluate the role of prostaglandin E receptor 4 (EP4) in MSC mediated cell proliferation under hypoxia, we manipulated the levels of EP4 in HCC cells via small interfering RNA (siRNA), EP4 antagonist or agonist.ResultsWe found that MSC under hypoxia condition (hypo-MSC) could promote proliferation of HCC cell lines and tumor growth in xenograft model. Hypoxia increased COX2 expression in MSC and promoted the secretion of prostaglandin E2 (PGE2), which then activated YAP in HCC cells and led to increased cell proliferation. Meanwhile, YAP activation enhanced lipogenesis in HCC cell lines by upregulating AKT/mTOR/SREBP1 pathway. Knockdown or overexpression of YAP significantly decreased or increased lipogenesis. Finally, EP4 was found to mediate the effects of hypo-MSC on YAP activation and lipogenesis of HCC cells.ConclusionsHypo-MSC can promote HCC progression by activating YAP and the YAP mediated lipogenesis through COX2/PGE2/EP4 axis. The communication between MSC and cancer cells may be a potential therapeutic target for inhibiting cancer growth.

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Tuftelin 1 Facilitates Hepatocellular Carcinoma Progression through Regulation of Lipogenesis and Focal Adhesion Maturation.

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