Hippo inactivation feeds tumor-initiating cells

ABSTRACT: The Hippo pathway has emerged as a well-conserved kinase cascade controlling cell proliferation and survival and has recently gained much attention for its key activity as a tumor suppressor. In a study published in Cell, Cordenonsi and colleagues link TAZ, a downstream effector of the Hippo pathway, to attributes of putative breast cancer stem cells, epithelial-to-mesenchymal transition and cell polarity.     

Hippo-TAZ 信号通路在乳腺癌及乳腺癌干细胞中的作用

Hippo 信号通路在调节器官生长、组织再生、肿瘤发生、发展中起重要作用,而含有 PDZ 结合模序转录共激活因子（TAZ）是其下游核心转录因子,参与整个信号通路的调控。近年来,研究者发现TAZ 过表达与乳腺癌的发生、发展、预后都有着密切的关系。探讨 Hippo 信号通路中 TAZ 与乳腺癌及乳腺癌干细胞的关系,可为乳腺癌诊断和治疗提供新的思路。     

PAR1 participates in the ability of multidrug resistance and tumorigenesis by controlling Hippo-YAP pathway

The Hippo pathway significantly correlates with organ size control and tumorigenesis. The activity of YAP/TAZ, a transducer of the Hippo pathway, is required to sustain self-renewal and tumor-initiation capacities in cancer stem cells (CSCs). But, upstream signals that control the mammalian Hippo pathway have not been well understood. Here, we reveal a connection between the Protease-activated receptor 1 (PAR1) signaling pathway and the Hippo-YAP pathway in gastric cancer stem-like cells. The selective PAR1 agonist TFLLR-NH₂ induces an increase in the fraction of side population cells which is enriched in CSCs, and promotes tumorigenesis, multi cancer drug resistance, cell morphological change, and cell invasion which are characteristics of CSCs. In addition, PAR1 activation inhibits the Hippo-YAP pathway kinase Lats via Rho GTPase. Lats kinase inhibition in turn results in increased nuclear localization of dephosphorylated YAP. Furthermore, PAR1 activation confers CSCs related traits via the Hippo-YAP pathway, and the Hippo-YAP pathway correlates with epithelial mesenchymal transition which is induced by PAR1 activation. Our research suggests that the PAR1 signaling deeply participates in the ability of multi drug resistance and tumorigenesis through interactions with the Hippo-YAP pathway signaling in gastric cancer stem-like cells. We presume that inhibited YAP is a new therapeutic target in the treatment human gastric cancer invasion and metastasis by dysregulated PAR1 or its agonists. The Hippo pathway significantly correlates with organ size control and tumorigenesis. The activity of YAP/TAZ, a transducer of the Hippo pathway, is required to sustain self-renewal and tumor-initiation capacities in cancer stem cells (CSCs). But, upstream signals that control the mammalian Hippo pathway have not been well understood. Here, we reveal a connection between the Protease-activated receptor 1 (PAR1) signaling pathway and the Hippo-YAP pathway in gastric cancer stem-like cells. The selective PAR1 agonist TFLLR-NH₂ induces an increase in the fraction of side population cells which is enriched in CSCs, and promotes tumorigenesis, multi cancer drug resistance, cell morphological change, and cell invasion which are characteristics of CSCs. In addition, PAR1 activation inhibits the Hippo-YAP pathway kinase Lats via Rho GTPase. Lats kinase inhibition in turn results in increased nuclear localization of Dephosphorylated YAP. Furthermore, PAR1 activation confers CSCs related traits via the Hippo-YAP pathway, and the Hippo-YAP pathway correlates with epithelial mesenchymal transition which is induced by PAR1 activation. Our research suggests that the PAR1 signaling deeply participates in the ability of multi drug resistance and tumorigenesis through interactions with the Hippo-YAP pathway signaling in gastric cancer stem-like cells. We presume that inhibited YAP is a new therapeutic target in the treatment human gastric cancer invasion and metastasis by dysregulated PAR1 or its agonists.     

Hippo signaling in oval cells and hepatocarcinogenesis

Hepatocellular carcinoma (HCC) is one of the most common malignancies and the third leading cause of cancer mortality world wide. Despite continuing development of new therapies, the prognosis for patients with HCC remains extremely poor. In part, this may relate to molecular abnormalities that stimulate HCC tumorigenesis and also contribute to reduced sensitivity to standard treatment. Increasing evidence has revealed the importance of liver cancer stem cells in hepatocarcinogenesis. Although widely investigated, the signaling pathways important for liver cancer stem cells in liver tumor initiation and progression are poorly understood. The Hippo signaling pathway was identified in Drosophila as an essential regulator of cell proliferation and apoptosis. Recently, Hippo pathway has been implicated in multiple events during development and it has also been proposed to play a vital role in several tumor types, especially in hepatocellular carcinoma. Strong evidences also proved the significant role of the Hippo signaling pathway in oval cell activation. As suggested, hippo signaling has a dual regulation of Hippo in liver tumor suppression as well as transition of oval cells to fully differentiated hepatocytes. Delineation of the malfunction of Hippo signaling pathway in HCC may lead to better understanding of hepatocarcinogenesis, rational medical therapy for HCC and possible therapy for other tumors. Here, we provide a historical review of this potent growth-regulatory pathway in HCC and highlight outstanding questions that will likely be the focus of future investigation.     

MicroRNA-125a influences breast cancer stem cells by targeting leukemia inhibitory factor receptor which regulates the hippo signaling pathway

Cancer stem cells (CSC) are the main driving force behind cancer initiation and progression. The molecular mechanisms that regulate CSC properties are poorly understood. MicroRNAs (miRNAs) play a significant role in normal and cancer tissues. Here, we show that miRNA-125a indirectly regulates TAZ, an effector molecule in the Hippo pathway, through the leukemia inhibitory factor receptor (LIFR). The miR-125a→LIFR axis affected the homeostasis of nonmalignant and malignant breast epithelial stem cells through the Hippo signaling pathway. Inhibition of miR-125a in breast cancer cells led to a significant reduction in the CSC pool. In contrast, enhanced expression of miR-125a in nonmalignant breast epithelial cells resulted in significant expansion of the stem cell pool. Gain of function and loss of function of LIFR directly correlated with the inhibition and overexpression of miR-125a, respectively. Modulation of miR-125a led to a change in the activity of TAZ and its subcellular localization. We further demonstrated that miR-125a influenced stem cells by regulating Hippo signaling through LIFR in human primary breast cancer cells confirming the data obtained from established cell lines. We suggest that miR-125a could be a potential target against CSCs that maybe used along with the existing conventional therapies.     

Effects of the Hippo Signaling Pathway in Human Gastric Cancer

Background/Aim: The Hippo signaling pathway is a newly discovered and conserved signaling cascade,which regulates organ size control by governing cell proliferation and apoptosis. This study aimed to investigateits effects in human gastric cancer. Methods: Tumor tissues (n=60), adjacent non-tumor tissues (n=60) andnormal tissues (n=60) were obtained from the same patients with primary gastric cancer (GC). In addition,70 samples of chronic atrophic gastritis (CAG) tissues were obtained from patients with intestinal metaplasia(IM) by endoscopic biopsy. Hippo signaling molecules, including Mst1, Lats1, YAP1, TAZ, TEAD1, Oct4 andCDX2, were determined by quantitative polymerase chain reaction (qPCR). Protein expression of Mst1, Lats1,YAP1, TEAD1 and CDX2 was assessed by immunohistochemistry and Western blotting. Results: Mst1, Lats1and Oct4 mRNA expression showed an increasing tendency from GC tissues to normal gastric tissues, while themRNA expression of YAP1, TAZ and TEAD1 was up-regulated (all P<0.01). Mst1 and Lats1 protein expressionpresented a similar trend with their mRNA expression. In addition, YAP1 and TEAD1 protein expression in GCwas significantly higher than in the other groups (all P<0.01). CDX2 mRNA and protein expression in the CAGgroup were higher than in the other groups (all P<0.01). In GC, mRNA expression of Mst1, Lats1, Oct4, YAP1,TAZ, TEAD1 and CDX2 had a close correlation with lymphatic metastasis and tumor TNM stage (all P<0.01).Furthermore, protein expression of Mst1, Lats1 ,YAP1, TAZ, TEAD1 and CDX2 had a close correlation betweeneach other (P<0.05). Conclusion: The Hippo signaling pathway is involved in the development, progression andmetastasis of human gastric cancer. Therefore, manipulation of Hippo signaling molecules may be a potentialtherapeutic strategy for gastric cancer.     

A novel HMGA1-CCNE2-YAP axis regulates breast cancer aggressiveness

High Mobility Group A1 (HMGA1) is an architectural chromatin factor that promotes neoplastic transformation and progression. However, the mechanism by which HMGA1 exerts its oncogenic function is not fully understood. Here, we show that cyclin E2 (CCNE2) acts downstream of HMGA1 to regulate the motility and invasiveness of basal-like breast cancer cells by promoting the nuclear localization and activity of YAP, the downstream mediator of the Hippo pathway. Mechanistically, the activity of MST1/2 and LATS1/2, the core kinases of the Hippo pathway, are required for the HMGA1- and CCNE2-mediated regulation of YAP localization. In breast cancer patients, high levels of HMGA1 and CCNE2 expression are associated with the YAP/TAZ signature, supporting this connection. Moreover, we provide evidence that CDK inhibitors induce the translocation of YAP from the nucleus to the cytoplasm, resulting in a decrease in its activity. These findings reveal an association between HMGA1 and the Hippo pathway that is relevant to stem cell biology, tissue homeostasis, and cancer.     

Hippo信号通路作用分子TAZ在人骨肉瘤及骨肉瘤干细胞中的表达

目的：检测在人骨肉瘤组织、骨肉瘤MG63细胞及其干细胞中Hippo信号分子TAZ的表达情况,比较骨肉瘤细胞和骨肉瘤干细胞中 TAZ 的表达差异,并探讨其可能的临床意义。方法2010年1月至2012年1月在我院治疗的骨肉瘤患者中,选取原发骨肉瘤组织标本12例,复发的骨肉瘤标本6例,另选6例骨纤维结构不良组织作阴性对照,并贴壁培养骨肉瘤MG63细胞,采用免疫组化方法检测骨肉瘤组织和骨肉瘤MG63细胞中 TAZ 的表达情况;用无血清悬浮培养骨肉瘤 MG63细胞,分离并收集骨肉瘤细胞球,通过定量反转录-聚合酶链反应（ RT-PCR ）法检测骨肉瘤MG63细胞及骨肉瘤细胞球中胚胎干细胞标志基因（ Nanog, Oct4）和 Hippo 信号分子 TAZ 的表达,Western 印记法检测 MG63细胞和细胞球中 TAZ 蛋白的表达情况。结果在12例人骨肉瘤原发组织标本中,3例骨肉瘤组织TAZ表达阳性,而6例骨肉瘤复发组织中TAZ表达全部阳性,在骨肉瘤细胞MG63中TAZ分子表达也呈阳性,而骨纤维结果不良中全部表达阴性。与骨肉瘤MG63细胞相比,RT-PCR显示培养的骨肉瘤细胞球中干细胞标志基因Nanog,Oct4和Hippo信号分子TAZ明显高表达。Western blot 提示细胞球中 TAZ 蛋白表达明显高于骨肉瘤 MG63细胞。结论骨肉瘤组织中存在TAZ分子的表达,在复发骨肉瘤组织中呈高表达;在骨肉瘤细胞株中也存在TAZ分子的表达,而在干细胞中TAZ分子表达更高;提示其与骨肉瘤干细胞的特征具有一定的相关性。     

Hippo信号通路在肺癌中的研究进展

肺癌是全世界范围内肿瘤相关性死亡的首要原因,每年死亡人数超过100万人,占全球癌症死亡人数的五分之一.虽然目前在手术、放化疗、靶向治疗、免疫治疗肺癌方面取得了一定进展,但患者的预后仍不理想.因此,亟待寻找评价预后的分子标志物和肺癌的治疗新靶点,为肺癌患者提供生存获益的有效方法.近年来,Hippo信号通路逐渐成为国内外肿瘤研究领域中新兴且热门的研究方向.Hippo信号通路激活时,其核心组件MST/MOB、LATS 1/2等能抑制转录的共激活剂YAP/TAZ的转录,二者被磷酸化并滞留在细胞浆中,从而抑制肺癌的发生发展.因此Hippo信号通路在临床应用中的潜在价值也越来越受关注.本篇文章总结了Hippo信号通路核心组成元件及上下游调控因子在肺癌形成进展过程中的重要作用和分子机制,并对Hippo信号通路的研究前景进行展望.