Abstract
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.
Highlights
Tumor microenvironment (TME) plays a very important role in cancer progression
Hypo-mesenchymal stem cells (MSC) promotes the proliferation of hepatocellular carcinoma (HCC) cells both in vitro and in vivo To explore the effects of MSC under hypoxia condition on HCC cell proliferation, we performed cell counting kit-8 (CCK-8) assays and found that the condition medium (CM) of MSC under normoxia and hypoxia conditions could both promote HCC cells growth, but the hypo-MSC could increase cell growth more robustly (Fig. 1a)
These tumors showed higher Ki-67 levels compared to other groups, as revealed by IHC staining (Fig. 1f and Additional file 2: Figure S1). These findings demonstrated that hypo-MSC could promote HCC cell proliferation both in vitro and in vivo
Summary
Tumor 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. The link between MSC and tumor progression was established by the promoting effects from MSC on tumor growth and metastasis in mouse lymphoma, melanoma and breast cancer models when injected together with tumor cells. This effect is mainly mediated by the numerous factors and chemokines produced by MSC, such as transforming growth factor-β (TGFβ), CC-chemokine ligand 5 (CCL5), CXC-chemokine ligand 10 (CXCL10) and CXCL12 [1]. The role of MSC in HCC progression, especially under the hypoxia condition, has not been fully investigated
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