细胞质lncRNAs与肿瘤信号调控

Role of cytoplasmic lncRNAs in regulating cancer signaling pathways 细胞质lncRNAs与肿瘤信号调控 1 first-author †E-mail:fupeifen@hotmail.comlinaifu@zju.edu.cn †E-mail:fupeifen@hotmail.comlinaifu@zju.edu.cn fupeifen@hotmail.com 2 2 1 2 corresp ‡Corresponding Author ‡Corresponding Author †E-mail:fupeifen@hotmail.comlinaifu@zju.edu.cn †E-mail:fupeifen@hotmail.comlinaifu@zju.edu.cn fupeifen@hotmail.com The Breast Centre, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China The Breast Centre, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China MOE Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China MOE Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China Cancer remains a serious healthcare problem despite significant improvements in early detection and treatment approaches in the past few decades. Novel biomarkers for diagnosis and therapeutic strategies are urgently needed. In recent years, long noncoding RNAs (lncRNAs) have been reported to be aberrantly expressed in tumors and show crosstalk with key cancer-related signaling pathways. In this review, we summarized the current progress of research on cytoplasmic lncRNAs and their roles in regulating cancer signaling and tumor progression, further characterization of which may lead to effective approaches for cancer prevention and therapy. 恶性肿瘤疾病长期作为危害人类健康的重要隐患,目前针对重要信号调控通路的一系列靶向抑制剂在临床后期业已出现耐药现象,迫切要求人们在肿瘤生物学研究和靶向治疗方向不断寻找新的可替代性靶点.长链非编码RNAs(lncRNAs)作为最新关注的研究热点,其在肿瘤发生和转移中的重要调节功能不断被我们及相关学者重点报道.随着RNA通量深度测序等相关研究技术的推广和发展,使人们得以饱览赏析lncRNAs作为健康和疾病重要调节因子的宏观图谱.本综述总结了胞质lncRNAs在调节肿瘤重要信号通路中的研究进展及其在肿瘤发生发展中的作用,为癌症的预前预后和靶向治疗提供帮助. Long noncoding RNA (lncRNA) Cancer signaling Cancer therapy Biomarker 长链非编码RNAs(lncRNAs) 信号转导 肿瘤标志物 肿瘤靶点 Introduction 1 Long noncoding RNAs (lncRNAs) are noncoding RNAs with transcript lengths over 200 nucleotides (Gibb et al., 2011 2011 ; Ma et al., 2018 2018 ). LncRNAs are involved in various human diseases, including inflammatory pathologies, neurological diseases, and various types of cancers (Ponting et al., 2009 2009 ; Tano and Akimitsu, 2012 2012 ; Zheng et al., 2017 2017 ; Guo et al., 2018 2018 ; Sang et al., 2018 2018 ). Moreover, they are abnormally expressed in tumors and play regulatory roles in cell physiological processes, including cell proliferation, migration, metastasis, and invasion in cancers (Lin et al., 2014a 2014a , 2017 2017 ; Xing et al., 2014 2014 ). Signaling pathways regulate a variety of cellular biological processes, which determine the traits of an organism (Gutschner and Diederichs, 2012 2012 ; Zheng et al., 2017 2017 ; Ma et al., 2018 2018 ; Sang et al., 2018 2018 ). In addition, it has been reported that almost all tumors exhibit dysfunctional signaling pathways (Pawson and Warner, 2007 2007 ). Aberrant activation of signaling pathways, including that of phosphoinositide 3-kinase (PI3K)/serine-threonine-protein kinase (AKT) (Lin et al., 2014a 2014a , 2014b 2014b ), Wnt (Angers and Moon, 2009 2009 ), Notch (Ntziachristos et al., 2014 2014 ), and Hippo/YAP (Li et al., 2017 2017 ), contributes to cancer cell proliferation, activation of angiogenesis, invasion, and metastasis. Increasing evidence has shown that lncRNAs are located in the cytosol and are involved in multiple signaling pathways (Prensner and Chinnaiyan, 2011 2011 ; Cheetham et al., 2013 2013 ). The crosstalk between the signaling pathways and lncRNAs greatly impacts disease progression (Wang et al., 2015 2015 ; Lin et al., 2017 2017 ; Yan et al., 2017 2017 ). There are many well-characterized lncRNAs that remodel signal transduction by various approaches, ranging from modulating components of signaling pathways to regulating the expression of targeted genes (Gutschner and Diederichs, 2012 2012 ; Yang et al., 2014 2014 ; Liu et al., 2015 2015 ). The regulatory roles of lncRNAs enable them to function as oncogenes or tumor-suppressor genes, regulating cancer signaling pathways positively or negatively, respectively, and thus, affecting disease progression. In this review, we provide an overview of the regulatory functions of lncRNAs in cancer signal transduction, and provide insights into the mechanisms by which these lncRNAs-associated pathways regulate tumor progression. Further exploration of the lncRNA-based signaling pathways will provide us an in-depth understanding of the molecular mechanism underlying various diseases and lay the foundation for development of new targeted therapeutic intervention for these diseases. LncRNAs-associated cancer signaling pathways 1 LncRNAs have been reported to be dysregulated in many types of cancers during tumor initiation, development, and progression (Batista and Chang, 2013 2013 ; Atala, 2014 2014 ; Sang et al., 2018 2018 ). However, understanding the function of individual lncRNAs in tumorigenesis remains challenging. Recently, we have elucidated a novel lncRNA-mediated signaling pathway in breast cancer metastasis. It indicated that lncRNA BCAR4 contributes to breast cancer metastasis via chemokine-induced binding of BCAR4 to two transcription factors having extended regulatory consequences. Moreover, BCAR4 wires up Hippo and Hedgehog signaling to reprogram glucose metabolism (Xing et al., 2014 2014 ; Zheng et al., 2017 2017 ). Besides, plasma lipid-associated lncRNA has been shown to regulate normoxic hypoxia-inducible factor 1α (HIF-1α) stabilization (Lin et al., 2016 2016 , 2017 2017 ). These studies highlighted a crucial role of lncRNAs in cancer-related signaling pathways. PI3K/AKT signaling pathway 2 The PI3K/AKT signaling pathway regulates many cellular processes, such as cell proliferation, survival, and migration (Luo et al., 2003 2003 ; Mayer and Arteaga, 2016 2016 ). This pathway is activated abnormally in many human malignancies, including breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, and endometrial cancer (Vivanco and Sawyers, 2002 2002 ; Altomare and Testa, 2005 2005 ; Hirai et al., 2010 2010 ). Interaction between phosphatidylinositol-3,4,5-trisphosphate (PIP3) and pleckstrin homology (PH) domain facilitates AKT phosphorylation at Ser473 and Thr308 by phosphoinositide-dependent protein kinase-1 (PDK1) and mammalian target of rapamycin (mTOR), respectively (Manning and Cantley, 2007 2007 ). The phosphorylated AKT is activated, which further activates its downstream substrates, thereby regulating tumor growth and metastasis (Citri and Yarden, 2006 2006 ). Long intergenic noncoding RNA for kinase activation ( LINK-A ) has been found to be highly expressed in breast cancer, and is associated with prognosis in breast cancer patients. It has been found that LINK-A interacts with PIP3 (Lin et al., 2017 2017 ). Although RNAs have been hypothesized to play essential roles during the origin of life, the role of RNAs in direct mediation of fundamental cellular processes remains largely unknown. Mechanistically, LINK-A directly promotes interactions between the plasma membrane phospholipid PtdIns(3,4,5)P 3 and AKT PH domain to facilitate the activation of AKT. LINK-A -dependent AKT hyperphosphorylation further activates its downstream substrates, resulting in tumor cell resistance to AKT inhibitors, and promoting tumorigenesis and metastasis. The deletion of the LINK-A -PIP3 binding motif renders breast cancer cells sensitive to AKT inhibitors. This PIP3-binding lncRNA regulates AKT activation with broad clinical significance. This study suggested an RNA molecule as a key mediator and catalyst involved in signal transduction, as well as a mediator of the related biological processes through direct association with lipids (Lin et al., 2017 2017 ). Further study also revealed gene amplification and a genetic variant (rs12095274: A > G) of LINK-A that significantly affects AKT activation and the outcome of breast cancer patients (Lin et al., 2017 2017 ). In further single nucleotide polymorphism (SNP) analysis, GG and AA genotypes were marked as homozygotes, and the AG genotype was marked as heterozygote. Analysis of 923 breast cancer samples showed that LINK-A was highly expressed in individuals with GG genotype, who also showed significantly higher breast cancer incidence and poorer survival time than individuals with AA genotype. Moreover, the SNP at this location showed different distribution in African, European, and Asian populations, suggesting that this lncRNA may have a role in physiology and pathology of human cancers. In light of the current lack of functional genetic association of lncRNAs with cancer, this study links an lncRNA-associated SNP to the regulation of AKT and its downstream oncogenic signaling. HIF-1α signaling pathway 2 HIFs are transcription factors that control energy, iron metabolism, erythropoiesis, and development, which are activated under hypoxic or pseudohypoxic conditions, and mediate adaptive responses of cells against these states (Pawson and Warner, 2007 2007 ; Kaelin and Ratcliffe, 2008 2008 ). HIFs consist of a stably expressed β-subunit and an oxygen-sensitive α-subunit, and is classified into three types: HIF-1α, HIF-2α, and HIF-3α (Kaelin and Ratcliffe, 2008 2008 ; Keith et al., 2011 2011 ). HIF-1α is expressed in all types of cells, and is significantly upregulated in most human cancers (Talks et al., 2000 2000 ). The expression of HIF-1α is significantly upregulated during malignancies. High level of HIF-1α promotes the transcription of genes involved in glucose and glutamine metabolism, and promotes angiogenesis and glycolysis (Denko, 2008 2008 ), which contributes to tumor proliferation and progress (Zhong et al., 1999 1999 ; Kuschel et al., 2012 2012 ). In addition, HIF-1α functionally interacts with many other signal transduction and transcription systems, including the NOTCH, WNT, and MYC pathways (Kaelin and Ratcliffe, 2008 2008 ). It has been reported that lncRNA LINK-A could promote triple-negative breast cancer (TNBC) tumorigenesis by regulating the HIF-1α-associated signaling pathway (Miah et al., 2012 2012 ; Schwab et al., 2012 2012 ). Mechanically, heparin-binding epidermal growth factor (HB-EGF)-mediated stimulation of EGF receptor (EGFR) and its consequent heterodimerization with the receptor glycoprotein nonmetastatic melanoma protein B (GPNMB) lead to the recruitment of a complex composed of LINK-A , breast tumor kinase (BRK), and leucine-rich repeat kinase 2 (LRRK2). LINK-A , a key signaling molecule, modifies the conformation of BRK and scaffolds LRRK2 kinases, which phosphorylates HIF-1α to promote its stabilization and transcriptional activity under normoxic conditions. This study revealed a novel HIF-1α regulatory mechanism functional under normoxic conditions, divergent from the classical view held in the field of cancer biology for decades (Lin et al., 2016 2016 ). This lncRNA-driven machinery highlights the magnitude and diversity of cytoplasmic lncRNAs in signal transduction. Clinically, monoclonal antibodies, small molecule inhibitors, and locked nucleic acids (LNAs) that target GPNMB, BRK, LINK-A , HIF-1α, and LRRK2 could all serve as promising therapeutic targets for TNBC treatment. The expression level of LINK-A , as well as the phosphorylation status of EGFR, GPNMB, BRK, and HIF-1α, could be considered as promising prognostic markers of TNBC patients, which would be of therapeutic significance. Hippo signaling pathway 2 Over the past few decades, the Hippo pathway has been established as a tumor suppressor pathway because it restricts proliferation and induces apoptosis (Pan, 2010 2010 ; Zhao et al., 2010 2010 ; Halder and Johnson, 2011 2011 ; Zhou et al., 2015 2015 ). Dysregulation of the Hippo pathway is associated with a broad spectrum of cancers (Pan, 2010 2010 ; Harvey et al., 2013 2013 ; Yu et al., 2015 2015 ). YAP has been identified as an oncoprotein associated with breast cancer (Overholtzer et al., 2006 2006 ) and is highly expressed in human breast cancer samples (Dong et al., 2007 2007 ; Zhou et al., 2015 2015 ). Loss of YAP suppresses oncogene-induced tumor growth in mouse mammary glands (Chen et al., 2014 2014 ). In addition, YAP promotes breast cancer cell survival and mobility (Wang et al., 2012 2012 ; Haskins et al., 2014 2014 ; Salah et al., 2014 2014 ; Song et al., 2015 2015 ). Similar to an earlier study (Overholtzer et al., 2006 2006 ), YAP overexpression in non-transformed mammary epithelial cells (i.e. MCF10A) led to epithelial-to-mesenchymal transition, suppression of apoptosis, growth factor-independent proliferation, and anchorage-independent growth (Wang et al., 2011 2011 , 2012 2012 ). Moreover, in vivo studies have also revealed the abilities of YAP (or its analog TAZ) in promoting human breast cancer metastasis, maintaining self-renewal and tumor-initiation capacities of breast cancer stem cells (Lian et al., 2010 2010 ; Cordenonsi et al., 2011 2011 ; Chen et al., 2012 2012 ; Beyer et al., 2013 2013 ). These findings not only revealed the critical roles of the Hippo-YAP pathway in human breast cancer development and progression, but, more importantly, also proposed YAP as a therapeutic target for breast cancer treatment. However, the detailed mechanisms beyond the restriction of cell proliferation and survival are yet to be fully understood, which could be explained by the lack of well-defined cellular functions of the downstream effector YAP. A previous study indicated that lncRNA MAYA mediated methylation and upstream kinase activity of MST1/2 in Hippo signaling, which consequently led to failure of LATS1 phosphorylation and activation of YAP1 target genes (Li et al., 2017 2017 ). A recent study also uncovered an lncRNA BCAR4 as a direct transcriptional target of YAP, which is involved in the YAP-dependent glycolysis. Mechanistically, long-term-activated YAP upregulated the transcription of BCAR4 , which, in turn, promoted the transcription of two glycolysis-related enzymes HK2 and PFKFB3, through Hedgehog effector GLI2/p300 complex-mediated histone acetylation marked by H3K27ac. Intriguingly, targeting the YAP- BCAR4 /Hedgehog-HK2/PFKFB3 axis using BCAR4 antisense-LNA or inhibitors of HK2 and PFKFB3 dramatically suppressed the YAP-dependent glycolysis and YAP-induced cell proliferation and tumorigenesis. Pathologically, the expression level of BCAR4 is positively correlated to YAP in breast cancer patient samples, in which low expression of both BCAR4 and YAP favors the recurrence-free survival rate of breast cancer patients. This study revealed that lncRNA BCAR4 is an essential downstream mediator of the Hippo-YAP pathway, involved in reprogramming glucose metabolism, which will potentially transform the prevailing dogma of cancer signaling and metabolism. Moreover, the identification of a new YAP- BCAR4 /Hedgehog-glycolysis signaling axis in breast cancer also provides additional therapeutic targets for breast cancer patients. Conclusions and perspective 1 There have been a number of studies reporting that dysregulation of lncRNAs and related signaling pathways are tightly associated with tumor cells or immune cells (Table 1 1 ). These lncRNAs could be considered as biomarkers for diagnosis and prognosis (Wapinski and Chang, 2011 2011 ; Ling et al., 2013 2013 ). For example, lnc-DC has been indicated to bind to STAT3 in the cytoplasm and prevent its dephosphorylation by SHP1, serving as an indicator for development of dendritic cells (DCs) (Wang et al., 2014 2014 ). LncRNA NKILA regulates IκB kinase (IKK)-induced inhibitor of NF-κB (IκB) phosphorylation and nuclear factor-κB (NF-κB) activation, indicating its essential roles in cancer metastasis (Liu et al., 2015 2015 ). H19 interacts with p53 and induces p53 inactivation, and its upregulation promotes gastric cancer (GC) cell proliferation and GC tumor progression, suggesting that H19 status in tumors may be a useful tool for detecting prognosis of a patient suffering from GC (Hadji et al., 2016 2016 ). HIF-1α: hypoxia-inducible factor 1α; HB-EGF: heparin-binding epidermal growth factor; EGFR: EGF receptor; GPNMB: glycoprotein nonmetastatic melanoma protein B; PI3K: phosphoinositide 3-kinase; AKT: serine-threonine-protein kinase; STAT3: signal transducers and activators of transcription 3; NF-κB: nuclear factor-κB; IκB: inhibitor of NF-κB; IKK: IκB kinase; GOT2: glutamate-oxaloacetate transaminase 2; IFN: interferon; RIG-I: retinoic acid-inducible gene I Gene Main distribution Related signaling pathway Mechanism Reference 2 LINK-A 2 Triple-negative breast tumor HIF-1α Mediates HB-EGF triggered, EGFR:GPNMB heterodimer-dependent HIF-1α phosphorylation, leading to HIF-1α stabilization and activation of HIF-1α transcriptional programs Lin et al., 2016 2016 PI3K/AKT Contributes to the AKT-PIP3 interaction and enhances EGF-induced AKT kinase activity Lin et al., 2017 2017 MAYA Majority of human solid tumors Hippo-YAP HER3-LLGL2- MAYA -NSUN6 complex methylates MST1 to activate YAP and target genes Li et al., 2017 2017 Lnc-DC Dendritic cells STAT3 Promotes STAT3 phosphorylation Zhong et al., 1999 1999 NKILA Normal breast epithelia or non-invasive breast tumors NF-κB Inhibits IKK-induced IκB phosphorylation to restrain NF-κB activity Liu et al., 2015 2015 ACOD1 Most of the cells and organs GOT2 metabolic pathway Binds the metabolic enzyme GOT2 and enhances its catalytic activity Wang et al., 2017 2017 Lnc-Lsm3b Immune cells and organs IFN I Binds to RIG-I and inhibits its activation to terminate type I IFN production Jiang et al., 2018 2018 The incidence and mortality of cancers, including lung cancer and breast cancer, have increased significantly recently and are expected to continue to rise in the coming decades. Thus, it will be extremely urgent to develop techniques for early diagnosis for efficient cancer treatment. Recently, lncRNAs, which are contributing to human pathogenesis, have attracted increased attention. LncRNAs have rapidly emerged as crucial regulators that interact with signaling pathways and control many cellular processes. The aberrant expression of lncRNAs has been shown to promote tumor progression in various types of cancers, including breast, liver, and kidney cancers, highlighting their therapeutic potential. LncRNAs could interact with signaling molecules, and activate signaling pathways influencing tumor initiation and progression (Wang et al., 2014 2014 ; Liu et al., 2015 2015 ; Lin et al., 2016 2016 , 2017 2017 ; Li et al., 2017 2017 ; Zheng et al., 2017 2017 ). The aberrant expression of lncRNAs in tumors and the related cancer signaling pathways have greatly impacted tumorigenesis in multiple types of cancers. Therefore, a better understanding of the function and molecular mechanism of lncRNAs will help us in not only identifying useful biomarkers for the diagnosis but also developing effective therapeutic targets for cancer treatment. References DA Altomare , JR Testa . Perturbations of the AKT signaling pathway in human cancer . Oncogene , 2005 . 24 ( 50 ): 7455 - 7464 . 16288292 DOI: 10.1038/sj.onc.1209085 http://doi.org/10.1038/sj.onc.1209085 . Perturbations of the AKT signaling pathway in human cancer S Angers , RT Moon . Proximal events in Wnt signal transduction . Nat Rev Mol Cell Biol , 2009 . 10 ( 7 ): 468 - 477 . 19536106 DOI: 10.1038/nrm2717 http://doi.org/10.1038/nrm2717 . Proximal events in Wnt signal transduction A Atala . Re: lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs . J Urol , 2014 . 191 ( 5 ): 1470 - 1471 . DOI: 10.1016/j.juro.2014.02.011 http://doi.org/10.1016/j.juro.2014.02.011 . Re: lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs PJ Batista , HY Chang . Long noncoding RNAs: cellular address codes in development and disease . Cell , 2013 . 152 ( 6 ): 1298 - 1307 . 23498938 DOI: 10.1016/j.cell.2013.02.012 http://doi.org/10.1016/j.cell.2013.02.012 . Long noncoding RNAs: cellular address codes in development and disease TA Beyer , A Weiss , Y Khomchuk , 等 . Switch enhancers interpret TGF-β and Hippo signaling to control cell fate in human embryonic stem cells . Cell Rep , 2013 . 5 ( 6 ): 1611 - 1624 . 24332857 DOI: 10.1016/j.celrep.2013.11.021 http://doi.org/10.1016/j.celrep.2013.11.021 . Switch enhancers interpret TGF-β and Hippo signaling to control cell fate in human embryonic stem cells SW Cheetham , F Gruhl , JS Mattick , 等 . Long noncoding RNAs and the genetics of cancer . Br J Cancer , 2013 . 108 ( 12 ): 2419 - 2425 . 23660942 DOI: 10.1038/bjc.2013.233 http://doi.org/10.1038/bjc.2013.233 . Long noncoding RNAs and the genetics of cancer DH Chen , YT Sun , YK Wei , 等 . LIFR is a breast cancer metastasis suppressor upstream of the Hippo-YAP pathway and a prognostic marker . Nat Med , 2012 . 18 ( 10 ): 1511 - 1517 . 23001183 DOI: 10.1038/nm.2940 http://doi.org/10.1038/nm.2940 . LIFR is a breast cancer metastasis suppressor upstream of the Hippo-YAP pathway and a prognostic marker Q Chen , NL Zhang , RS Gray , 等 . A temporal requirement for Hippo signaling in mammary gland differentiation, growth, and tumorigenesis . Genes Dev , 2014 . 28 ( 5 ): 432 - 437 . 24589775 DOI: 10.1101/gad.233676.113 http://doi.org/10.1101/gad.233676.113 . A temporal requirement for Hippo signaling in mammary gland differentiation, growth, and tumorigenesis A Citri , Y Yarden . EGF-ERBB signalling: towards the systems level . Nat Rev Mol Cell Biol , 2006 . 7 ( 7 ): 505 - 516 . 16829981 DOI: 10.1038/nrm1962 http://doi.org/10.1038/nrm1962 . EGF-ERBB signalling: towards the systems level M Cordenonsi , F Zanconato , L Azzolin , 等 . The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells . Cell , 2011 . 147 ( 4 ): 759 - 772 . 22078877 DOI: 10.1016/j.cell.2011.09.048 http://doi.org/10.1016/j.cell.2011.09.048 . The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells NC Denko . Hypoxia, HIF1 and glucose metabolism in the solid tumour . Nat Rev Cancer , 2008 . 8 ( 9 ): 705 - 713 . 19143055 DOI: 10.1038/nrc2468 http://doi.org/10.1038/nrc2468 . Hypoxia, HIF1 and glucose metabolism in the solid tumour JX Dong , G Feldmann , JB Huang , 等 . Elucidation of a universal size-control mechanism in Drosophila and mammals . Cell , 2007 . 130 ( 6 ): 1120 - 1133 . 17889654 DOI: 10.1016/j.cell.2007.07.019 http://doi.org/10.1016/j.cell.2007.07.019 . Elucidation of a universal size-control mechanism in Drosophila and mammals EA Gibb , CJ Brown , WL Lam . The functional role of long non-coding RNA in human carcinomas . Mol Cancer, 10:38 , 2011 . DOI: 10.1186/1476-4598-10-38 http://doi.org/10.1186/1476-4598-10-38 . The functional role of long non-coding RNA in human carcinomas YZ Guo , HH Sun , XT Wang , 等 . Transcriptomic analysis reveals key lncRNAs associated with ribosomal biogenesis and epidermis differentiation in head and neck squamous cell carcinoma . J Zhejiang Univ-Sci B (Biomed & Biotechnol) , 2018 . 19 ( 9 ): 674 - 688 . DOI: 10.1631/jzus.B1700319 http://doi.org/10.1631/jzus.B1700319 . Transcriptomic analysis reveals key lncRNAs associated with ribosomal biogenesis and epidermis differentiation in head and neck squamous cell carcinoma T Gutschner , S Diederichs . The hallmarks of cancer: a long non-coding RNA point of view . RNA Biol , 2012 . 9 ( 6 ): 703 - 719 . 22664915 DOI: 10.4161/rna.20481 http://doi.org/10.4161/rna.20481 . The hallmarks of cancer: a long non-coding RNA point of view F Hadji , MC Boulanger , SP Guay , 等 . Altered DNA methylation of long noncoding RNA H19 in calcific aortic valve disease promotes mineralization by silencing NOTCH1 . Circulation , 2016 . 134 ( 23 ): 1848 - 1862 . 27789555 DOI: 10.1161/CIRCULATIONAHA.116.023116 http://doi.org/10.1161/CIRCULATIONAHA.116.023116 . Altered DNA methylation of long noncoding RNA H19 in calcific aortic valve disease promotes mineralization by silencing NOTCH1 G Halder , RL Johnson . Hippo signaling: growth control and beyond . Development , 2011 . 138 ( 1 ): 9 - 22 . 21138973 DOI: 10.1242/dev.045500 http://doi.org/10.1242/dev.045500 . Hippo signaling: growth control and beyond KF Harvey , XM Zhang , DM Thomas . The Hippo pathway and human cancer . Nat Rev Cancer , 2013 . 13 ( 4 ): 246 - 257 . 23467301 DOI: 10.1038/nrc3458 http://doi.org/10.1038/nrc3458 . The Hippo pathway and human cancer JW Haskins , DX Nguyen , DF Stern . Neuregulin 1-activated ERBB4 interacts with YAP to induce Hippo pathway target genes and promote cell migration . Sci Signal , 2014 . 7 ( 355 ): ra116 25492965 DOI: 10.1126/scisignal.2005770 http://doi.org/10.1126/scisignal.2005770 . Neuregulin 1-activated ERBB4 interacts with YAP to induce Hippo pathway target genes and promote cell migration H Hirai , H Sootome , Y Nakatsuru , 等 . MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo . Mol Cancer Ther , 2010 . 9 ( 7 ): 1956 - 1967 . 20571069 DOI: 10.1158/1535-7163.MCT-09-1012 http://doi.org/10.1158/1535-7163.MCT-09-1012 . MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo MH Jiang , SK Zhang , ZH Yang , 等 . Self-recognition of an inducible host lncRNA by RIG-I feedback restricts innate immune response . Cell , 2018 . 173 ( 4 ): 906 - 919e13 . 29706547 DOI: 10.1016/j.cell.2018.03.064 http://doi.org/10.1016/j.cell.2018.03.064 . Self-recognition of an inducible host lncRNA by RIG-I feedback restricts innate immune response Jr WG Kaelin , PJ Ratcliffe . Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway . Mol Cell , 2008 . 30 ( 4 ): 393 - 402 . 18498744 DOI: 10.1016/j.molcel.2008.04.009 http://doi.org/10.1016/j.molcel.2008.04.009 . Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway B Keith , RS Johnson , MC Simon . HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression . Nat Rev Cancer , 2011 . 12 ( 1 ): 9 - 22 . 22169972 DOI: 10.1038/nrc3183 http://doi.org/10.1038/nrc3183 . HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression A Kuschel , P Simon , S Tug . Functional regulation of HIF-1α under normoxia–is there more than post-translational regulation? . J Cell Physiol , 2012 . 227 ( 2 ): 514 - 524 . 21503885 DOI: 10.1002/jcp.22798 http://doi.org/10.1002/jcp.22798 . Functional regulation of HIF-1α under normoxia–is there more than post-translational regulation? CL Li , SY Wang , Z Xing , 等 . A ROR1-HER3-lncRNA signalling axis modulates the Hippo-YAP pathway to regulate bone metastasis . Nat Cell Biol , 2017 . 19 ( 2 ): 106 - 119 . 28114269 DOI: 10.1038/ncb3464 http://doi.org/10.1038/ncb3464 . A ROR1-HER3-lncRNA signalling axis modulates the Hippo-YAP pathway to regulate bone metastasis I Lian , J Kim , H Okazawa , 等 . The role of YAP transcription coactivator in regulating stem cell self-renewal and differentiation . Genes Dev , 2010 . 24 ( 11 ): 1106 - 1118 . 20516196 DOI: 10.1101/gad.1903310 http://doi.org/10.1101/gad.1903310 . The role of YAP transcription coactivator in regulating stem cell self-renewal and differentiation AF Lin , HL Piao , L Zhuang , 等 . FoxO transcription factors promote AKT Ser473 phosphorylation and renal tumor growth in response to pharmacologic inhibition of the PI3K-AKT pathway . Cancer Res , 2014 . 74 ( 6 ): 1682 - 1693 . 24448243 DOI: 10.1158/0008-5472.CAN-13-1729 http://doi.org/10.1158/0008-5472.CAN-13-1729 . FoxO transcription factors promote AKT Ser473 phosphorylation and renal tumor growth in response to pharmacologic inhibition of the PI3K-AKT pathway AF Lin , J Yao , L Zhuang , 等 . The FoxO-BNIP3 axis exerts a unique regulation of mTORC1 and cell survival under energy stress . Oncogene , 2014 . 33 ( 24 ): 3183 - 3194 . 23851496 DOI: 10.1038/onc.2013.273 http://doi.org/10.1038/onc.2013.273 . The FoxO-BNIP3 axis exerts a unique regulation of mTORC1 and cell survival under energy stress AF Lin , CL Li , Z Xing , 等 . The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer . Nat Cell Biol , 2016 . 18 ( 2 ): 213 - 224 . 26751287 DOI: 10.1038/ncb3295 http://doi.org/10.1038/ncb3295 . The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer AF Lin , QS Hu , CL Li , 等 . The LINK-A lncRNA interacts with PtdIns(3,4,5)P 3 to hyperactivate AKT and confer resistance to AKT inhibitors . Nat Cell Biol , 2017 . 19 ( 3 ): 238 - 251 . 28218907 DOI: 10.1038/ncb3473 http://doi.org/10.1038/ncb3473 . The LINK-A lncRNA interacts with PtdIns(3,4,5)P3 to hyperactivate AKT and confer resistance to AKT inhibitors H Ling , R Spizzo , Y Atlasi , 等 . Ccat2 , a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer . Genome Res , 2013 . 23 ( 9 ): 1446 - 1461 . 23796952 DOI: 10.1101/gr.152942.112 http://doi.org/10.1101/gr.152942.112 . Ccat2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer BD Liu , LJ Sun , Q Liu , 等 . A cytoplasmic NF-κB interacting long noncoding RNA blocks IκB phosphorylation and suppresses breast cancer metastasis . Cancer Cell , 2015 . 27 ( 3 ): 370 - 381 . 25759022 DOI: 10.1016/j.ccell.2015.02.004 http://doi.org/10.1016/j.ccell.2015.02.004 . A cytoplasmic NF-κB interacting long noncoding RNA blocks IκB phosphorylation and suppresses breast cancer metastasis J Luo , BD Manning , LC Cantley . Targeting the PI3K-Akt pathway in human cancer: rationale and promise . Cancer Cell , 2003 . 4 ( 4 ): 257 - 262 . 14585353 DOI: 10.1016/S1535-6108(03)00248-4 http://doi.org/10.1016/S1535-6108(03)00248-4 . Targeting the PI3K-Akt pathway in human cancer: rationale and promise YX Ma , JM Zhang , LX Wen , 等 . Membrane-lipid associated lncRNA: a new regulator in cancer signaling . Cancer Lett , 2018 . 419 27 - 29 . 29330108 DOI: 10.1016/j.canlet.2018.01.008 http://doi.org/10.1016/j.canlet.2018.01.008 . Membrane-lipid associated lncRNA: a new regulator in cancer signaling BD Manning , LC Cantley . AKT/PKB signaling: navigating downstream . Cell , 2007 . 129 ( 7 ): 1261 - 1274 . 17604717 DOI: 10.1016/j.cell.2007.06.009 http://doi.org/10.1016/j.cell.2007.06.009 . AKT/PKB signaling: navigating downstream IA Mayer , CL Arteaga . The PI3K/AKT pathway as a target for cancer treatment . Ann Rev Med , 2016 . 67 11 - 28 . 26473415 DOI: 10.1146/annurev-med-062913-051343 http://doi.org/10.1146/annurev-med-062913-051343 . The PI3K/AKT pathway as a target for cancer treatment S Miah , A Martin , KE Lukong . Constitutive activation of breast tumor kinase accelerates cell migration and tumor growth in vivo . Oncogenesis, 1:e11 , 2012 . DOI: 10.1038/oncsis.2012.11 http://doi.org/10.1038/oncsis.2012.11 . Constitutive activation of breast tumor kinase accelerates cell migration and tumor growth in vivo P Ntziachristos , JS Lim , J Sage , 等 . From fly wings to targeted cancer therapies: a centennial for notch signaling . Cancer Cell , 2014 . 25 ( 3 ): 318 - 334 . 24651013 DOI: 10.1016/j.ccr.2014.02.018 http://doi.org/10.1016/j.ccr.2014.02.018 . From fly wings to targeted cancer therapies: a centennial for notch signaling M Overholtzer , JM Zhang , GA Smolen , 等 . Transforming properties of YAP , a candidate oncogene on the chromosome 11q22 amplicon . Proc Natl Acad Sci USA , 2006 . 103 ( 33 ): 12405 - 12410 . DOI: 10.1073/pnas.0605579103 http://doi.org/10.1073/pnas.0605579103 . Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon DJ Pan . The Hippo signaling pathway in development and cancer . Dev Cell , 2010 . 19 ( 4 ): 491 - 505 . 20951342 DOI: 10.1016/j.devcel.2010.09.011 http://doi.org/10.1016/j.devcel.2010.09.011 . The Hippo signaling pathway in development and cancer T Pawson , N Warner . Oncogenic re-wiring of cellular signaling pathways . Oncogene , 2007 . 26 ( 9 ): 1268 - 1275 . 17322911 DOI: 10.1038/sj.onc.1210255 http://doi.org/10.1038/sj.onc.1210255 . Oncogenic re-wiring of cellular signaling pathways CP Ponting , PL Oliver , W Reik . Evolution and functions of long noncoding RNAs . Cell , 2009 . 136 ( 4 ): 629 - 641 . 19239885 DOI: 10.1016/j.cell.2009.02.006 http://doi.org/10.1016/j.cell.2009.02.006 . Evolution and functions of long noncoding RNAs JR Prensner , AM Chinnaiyan . The emergence of lncRNAs in cancer biology . Cancer Discov , 2011 . 1 ( 5 ): 391 - 407 . 22096659 DOI: 10.1158/2159-8290.CD-11-0209 http://doi.org/10.1158/2159-8290.CD-11-0209 . The emergence of lncRNAs in cancer biology Z Salah , E Itzhaki , RI Aqeilan . The ubiquitin E3 ligase ITCH enhances breast tumor progression by inhibiting the Hippo tumor suppressor pathway . Oncotarget , 2014 . 5 ( 21 ): 10886 - 10900 . 25350971 . The ubiquitin E3 ligase ITCH enhances breast tumor progression by inhibiting the Hippo tumor suppressor pathway LJ Sang , HQ Ju , GP Liu , 等 . LncRNA Camk - A regulates Ca 2+ -signaling-mediated tumor microenvironment remodeling . Mol Cell , 2018 . 72 ( 1 ): 71 - 83e7 . 30220561 . LncRNA Camk-A regulates Ca2+-signaling-mediated tumor microenvironment remodeling LP Schwab , DL Peacock , D Majumdar , 等 . Hypoxia-inducible factor 1α promotes primary tumor growth and tumor-initiating cell activity in breast cancer . Breast Cancer Res , 2012 . 14 ( 1 ): R6 22225988 DOI: 10.1186/bcr3087 http://doi.org/10.1186/bcr3087 . Hypoxia-inducible factor 1α promotes primary tumor growth and tumor-initiating cell activity in breast cancer QH Song , BB Mao , JB Cheng , 等 . YAP enhances autophagic flux to promote breast cancer cell survival in response to nutrient deprivation . PLoS ONE , 2015 . 10 ( 3 ): e0120790 25811979 DOI: 10.1371/journal.pone.0120790 http://doi.org/10.1371/journal.pone.0120790 . YAP enhances autophagic flux to promote breast cancer cell survival in response to nutrient deprivation KL Talks , H Turley , KC Gatter , 等 . The expression and distribution of the hypoxia-inducible factors HIF-1α and HIF-2α in normal human tissues, cancers, and tumor-associated macrophages . Am J Pathol , 2000 . 157 ( 2 ): 411 - 421 . 10934146 DOI: 10.1016/S0002-9440(10)64554-3 http://doi.org/10.1016/S0002-9440(10)64554-3 . The expression and distribution of the hypoxia-inducible factors HIF-1α and HIF-2α in normal human tissues, cancers, and tumor-associated macrophages K Tano , N Akimitsu . Long non-coding RNAs in cancer progression . Front Genet, 3:219 , 2012 . DOI: 10.3389/fgene.2012.00219 http://doi.org/10.3389/fgene.2012.00219 . Long non-coding RNAs in cancer progression I Vivanco , CL Sawyers . The phosphatidylinositol 3-kinase-AKT pathway in human cancer . Nat Rev Cancer , 2002 . 2 ( 7 ): 489 - 501 . 12094235 DOI: 10.1038/nrc839 http://doi.org/10.1038/nrc839 . The phosphatidylinositol 3-kinase-AKT pathway in human cancer P Wang , YQ Xue , YM Han , 等 . The STAT3-binding long noncoding RNA lnc-DC controls human dendritic cell differentiation . Science , 2014 . 344 ( 6181 ): 310 - 313 . 24744378 DOI: 10.1126/science.1251456 http://doi.org/10.1126/science.1251456 . The STAT3-binding long noncoding RNA lnc-DC controls human dendritic cell differentiation P Wang , JF Xu , YJ Wang , 等 . An interferon-independent lncRNA promotes viral replication by modulating cellular metabolism . Science , 2017 . 358 ( 6366 ): 1051 - 1055 . 29074580 DOI: 10.1126/science.aao0409 http://doi.org/10.1126/science.aao0409 . An interferon-independent lncRNA promotes viral replication by modulating cellular metabolism WQ Wang , J Huang , JJ Chen . Angiomotin-like proteins associate with and negatively regulate YAP1 . J Biol Chem , 2011 . 286 ( 6 ): 4364 - 4370 . 21187284 DOI: 10.1074/jbc.C110.205401 http://doi.org/10.1074/jbc.C110.205401 . Angiomotin-like proteins associate with and negatively regulate YAP1 WQ Wang , J Huang , X Wang , 等 . PTPN14 is required for the density-dependent control of YAP1 . Genes Dev , 2012 . 26 ( 17 ): 1959 - 1971 . 22948661 DOI: 10.1101/gad.192955.112 http://doi.org/10.1101/gad.192955.112 . PTPN14 is required for the density-dependent control of YAP1 YY Wang , L He , Y Du , 等 . The long noncoding RNA lncTCF 7 promotes self-renewal of human liver cancer stem cells through activation of Wnt signaling . Cell Stem Cell , 2015 . 16 ( 4 ): 413 - 425 . 25842979 DOI: 10.1016/j.stem.2015.03.003 http://doi.org/10.1016/j.stem.2015.03.003 . The long noncoding RNA lncTCF7 promotes self-renewal of human liver cancer stem cells through activation of Wnt signaling O Wapinski , HY Chang . Long noncoding RNAs and human disease . Trends Cell Biol , 2011 . 21 ( 6 ): 354 - 361 . 21550244 DOI: 10.1016/j.tcb.2011.04.001 http://doi.org/10.1016/j.tcb.2011.04.001 . Long noncoding RNAs and human disease Z Xing , AF Lin , CL Li , 等 . lncRNA directs cooperative epigenetic regulation downstream of chemokine signals . Cell , 2014 . 159 ( 5 ): 1110 - 1125 . 25416949 DOI: 10.1016/j.cell.2014.10.013 http://doi.org/10.1016/j.cell.2014.10.013 . lncRNA directs cooperative epigenetic regulation downstream of chemokine signals K Yan , J Tian , W Shi , 等 . LncRNA SNHG6 is associated with poor prognosis of gastric cancer and promotes cell proliferation and EMT through epigenetically silencing p27 and sponging miR-101-3p . Cell Physiol Biochem , 2017 . 42 ( 3 ): 999 - 1012 . 28683446 DOI: 10.1159/000478682 http://doi.org/10.1159/000478682 . LncRNA SNHG6 is associated with poor prognosis of gastric cancer and promotes cell proliferation and EMT through epigenetically silencing p27 and sponging miR-101-3p GD Yang , XZ Lu , LJ Yuan . LncRNA: a link between RNA and cancer . Biochim Biophys Acta , 2014 . 1839 ( 11 ): 1097 - 1109 . 25159663 DOI: 10.1016/j.bbagrm.2014.08.012 http://doi.org/10.1016/j.bbagrm.2014.08.012 . LncRNA: a link between RNA and cancer FX Yu , B Zhao , KL Guan . Hippo pathway in organ size control, tissue homeostasis, and cancer . Cell , 2015 . 163 ( 4 ): 811 - 828 . 26544935 DOI: 10.1016/j.cell.2015.10.044 http://doi.org/10.1016/j.cell.2015.10.044 . Hippo pathway in organ size control, tissue homeostasis, and cancer B Zhao , L Li , QY Lei , 等 . The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version . Genes Dev , 2010 . 24 ( 9 ): 862 - 874 . 20439427 DOI: 10.1101/gad.1909210 http://doi.org/10.1101/gad.1909210 . The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version X Zheng , H Han , GP Liu , 等 . LncRNA wires up Hippo and hedgehog signaling to reprogramme glucose metabolism . EMBO J , 2017 . 36 ( 22 ): 3325 - 3335 . 28963395 . LncRNA wires up Hippo and hedgehog signaling to reprogramme glucose metabolism H Zhong , AM de Marzo , E Laughner , 等 . Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases . Cancer Res , 1999 . 59 ( 22 ): 5830 - 5835 . 10582706 . Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases X Zhou , SY Wang , Z Wang , 等 . Estrogen regulates Hippo signaling via GPER in breast cancer . J Clin Invest , 2015 . 125 ( 5 ): 2123 - 2135 . 25893606 DOI: 10.1172/JCI79573 http://doi.org/10.1172/JCI79573 . Estrogen regulates Hippo signaling via GPER in breast cancer Compliance with ethics guidelines Pei-fen FU, Xin ZHENG, Xiao FAN, and Ai-fu LIN declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors. 10.1631/jzus.B1800254 Project supported by the National Natural Science Foundation of China (Nos. 81672791 and 81872300) and the Zhejiang Provincial Natural Science Foundation for Distinguished Young Scholars of China (No. LR18C060002) 2018-04-27 2018-09-16 2022-01-05 Copyright © Zhejiang University and Springer-Verlag GmbH Germany, part of Springer Nature 2019 2019 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 01 20