Role of cytoplasmic lncRNAs in regulating cancer signaling pathways

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. 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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