The hypoxia conditioned mesenchymal stem cells promote hepatocellular carcinoma progression through YAP mediated lipogenesis reprogramming

Abstract

Background 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. As hypoxia is a common feature of TME, it is essential to investigate the effects of hypoxia on MSC during HCC progression. Methods The 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. Results We 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 E 2 (PGE 2 ), 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. Conclusions Hypo-MSC can promote HCC progression by activating YAP and the YAP mediated lipogenesis through COX2/PGE 2 /EP4 axis. The communication between MSC and cancer cells may be a potential therapeutic target for inhibiting cancer growth. Electronic supplementary material The online version of this article (10.1186/s13046-019-1219-7) contains supplementary material, which is available to authorized users.

RETRACTED ARTICLE: PHD2 acts as an oncogene through activation of Ras/Raf/MEK/ERK and JAK1/STAT3 pathways in human hepatocellular carcinoma cells

“…Hypoxic microenvironment is a common feature during the progression of HCC [4]. HCC cells can survive and rapidly proliferate even under hypoxic conditions.…”

“…In the clinic, the value of hypoxia as a tumour hallmark has been recognized and its level is correlated with tumour metastasis and poor survival in a broad spectrum of cancers [3]. Hepatocellular carcinoma (HCC) is one such solid tumour that hypoxic condition contributes a lot in the progression of tumours [4]. HCC is a common primary liver cancer with a high incidence of distal metastasis.…”

Eicosanoids in Cancer: Prostaglandin E2 Receptor 4 in Cancer Therapeutics and Immunotherapy

“…EP4 can mediate the effects of hypoxia-driven mesenchymal stem cells in the progression of hepatocellular carcinoma. This response is reversed in EP4 siRNA expressing cells or in the presence of GW627368x (Liu et al, 2019). The EP4 antagonist L161982 blocks the ability of enteric glial cells to stimulate colon CSCs via a PGE2/EP4/EGFRdependent pathway (Valès et al, 2019).…”

Interaction of head and neck squamous cell carcinoma cells and mesenchymal stem cells under hypoxia and normoxia

“…The interaction of tumor cells and MSCs under hypoxia is rarely examined. Recently, MSCs were shown to promote tumor cell proliferation after conditioning in hypoxic media (40).…”