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  In this article
 »  Abstract
 » Introduction
 »  Hippo Signaling ...
 »  Implication of Y...
 »  Implication of L...
 »  Implication of M...
 »  Upstream Signali...
 »  Downstream Signa...
 »  Targeting the Hi...
 » Future Perspectives
 »  References

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REVIEW ARTICLE
Year : 2015  |  Volume : 52  |  Issue : 5  |  Page : 1-5
 

Roles of Hippo signaling in lung cancer


1 Department of Hand Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
2 Department of Thyroid Surgery, Second Hospital of Jilin University, Changchun, China

Date of Web Publication3-Nov-2015

Correspondence Address:
H Zhang
Department of Hand Surgery, China-Japan Union Hospital of Jilin University, Changchun
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.168949

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 » Abstract 

Lung cancer is the leading cause of cancer-related mortality in the world, with more than 1 million deaths/year. Over the past years, lung cancer treatment has been based on cytotoxic agents and an improvement in the outcome and quality of life for patients has been observed. However, it has become clear that additional therapeutic strategies are urgently required to provide an improved survival benefit for patients. A major intracellular signaling pathway, the Hippo signaling pathways have been extensively studied in neoplasia, including lung cancer. Furthermore, the study of constitutively activated receptor and their downstream signaling mediators has become a promising new field of investigation for lung cancer treatment. Nevertheless for lung cancer, this approach has not been successful yet. Here, we will review the molecular basis of Hippo signaling in lung cancer and further discuss the therapeutic potential of multi-targeted strategies involving Yes-associated protein inhibitors.


Keywords: Lung cancer, Hippo pathway, Yes-associated protein


How to cite this article:
Wang Y, Ding W, Chen C, Niu Z, Pan M, Zhang H. Roles of Hippo signaling in lung cancer. Indian J Cancer 2015;52, Suppl S1:1-5

How to cite this URL:
Wang Y, Ding W, Chen C, Niu Z, Pan M, Zhang H. Roles of Hippo signaling in lung cancer. Indian J Cancer [serial online] 2015 [cited 2021 Jul 31];52, Suppl S1:1-5. Available from: https://www.indianjcancer.com/text.asp?2015/52/5/1/168949



 » Introduction Top


Lung cancer (both small cell and nonsmall cell) is one of the most common cancers in both men and women. Lung cancer accounts for approximately 26% of all cancer deaths and causes the death of 85% of newly diagnosed patients within 5 years.[1] Many lung cancer patients have a poor prognosis.[2] The high mortality and poor prognosis mainly attribute to the difficulty of early diagnosis. Worldwide over 1 million people die annually in consequence of lung cancer.[3] Approximately, 85% of these cases are nonsmall cell lung cancer (NSCLC) with the rest being SCLC.[4] Lung cancer development is related to tobacco smoking, exposure to asbestos, and other potential carcinogens. The main treatment options for people with lung cancer include surgery, radiofrequency ablation, radiation therapy, chemotherapy, targeted therapies, and immunotherapy. Palliative procedures can also alleviate symptoms. In many cases, more than one type of treatments is used. Recently, a growing body of evidence suggests that lung tumors selectively up-regulate different signaling pathways implicated in cell proliferation, survival, and angiogenesis, to become invasive and chemoresistant.[5]

The molecular mechanisms responsible for cancer development have been extensively studied, and the contribution of abnormal Hippo signaling to tumor growth, maintenance and invasion has been well documented. The Hippo signaling pathway controls organ size through the regulation of cell cycle, proliferation, and apoptosis.[6],[7] The Hippo pathway was initially identified and named through screenings for mutant tumor suppressors in flies, in which loss-of-function mutations of components of the Hippo pathway revealed robust overgrowth as a result of increased cell proliferation and decreased cell death.[8] The deregulation of Hippo signaling leads to a concurrent combination of uncontrolled cellular proliferation and inhibition of apoptosis – two key hallmarks in cancer development. In this review, we summarize the functions of the mammalian Hippo pathway in tumor formation, and then discuss lung cancer involving Hippo signaling core components with a specific focus on our current understanding of the cancer roles of MST1/2 and Yes-associated protein (YAP)/TAZ and large tumor suppressor (LATS). In addition, the possible pharmacological interventions with Hippo signaling will be reviewed, with particular emphasis on anticancer drug development and regenerative medicine.


 » Hippo Signaling Pathway Top


The central components of this pathway comprise a regulatory serine-threonine kinase module and a transcriptional module.[9] The kinase module includes serine/threonine kinase 3 and 4 (STK3 and 4, also called MST2 and 1, orthologs of Drosophila Hippo), SAV1, and serine/threonine kinase LATS1 and 2.[10] The transcriptional module includes YAP and transcriptional coactivator with PDZ-binding motif (TAZ, also known as WWTR1).[11],[12] YAP and TAZ when they are phosphorylated, are segregated in the cytoplasm and undergo protein degradation. Automatically, activated MST1/2 kinases associate with their scaffolding partner SAV and phosphorylate LATS1/2, resulting in increased LATS complex formation and LATS1/2 activation. LATS1/2 continues the kinase cascade by phosphorylating the transcriptional co-activator YAP and its vertebrate-specific paralog TAZ. Phosphorylated YAP (serine 127) is sequestered in the cytoplasm via a 14-3-3 protein family member, preventing it from entering the nucleus.[13] Phosphorylated YAP/TAZ cannot accumulate into the nucleus, and this hinders their co-transcriptional activity. The deregulation of Hippo pathway will lead to increased YAP/TAZ activity with an under phosphorylated form in the nucleus.[14] This will induce oncogenic transformation due to the activation of transcription factors including transcription enhancers activation domain (TEAD) family members.[15] The TEAD proteins are unable to activate gene transcription on their own; however, when YAP is present in the nucleus, they cooperate to promote transcription of a number of pro-proliferative and anti-apoptotic genes.[16] Below, we will summarize the current knowledge about the contribution and implication of the Hippo pathway in lung cancer development and maintenance, and further discuss multi-point pathway intervention as the therapy of choice.


 » Implication of Yes-Associated Protein/taz in Lung Cancer Top


Many lines of evidence point to the importance of deregulated Hippo signaling in lung cancer. YAP/TAZ are both highly expressed in NSCLC in humans. In addition, knocking down either YAP or TAZ in NSCLC cells is sufficient to inhibit proliferation, invasion, and growth in mice.[17] It has been shown that knockdown of either YAP or TAZ is sufficient to decrease cell migration in vitro and metastasis in vivo and expression of constitutively active YAP is sufficient to drive lung cancer progression in vivo.[18] Recent studies showed that TAZ was an oncogene in NSCLC. TAZ was over-expressed in NSCLC cells and over-expression of TAZ in HBE135 immortalized human bronchial epithelial cells caused increased cell proliferation and transformation. In addition, short-hairpin RNA-mediated knockdown of TAZ expression in NSCLC cells suppresses their proliferation and anchorage-independent growth in vitro, and tumor growth in mice in vivo, which can be reversed by re-introduction of shRNA-resistant TAZ into TAZ-knockdown NSCLC cells.[19] Similar results were found for TAZ paralog YAP, too.[17] The expression of the YAP protein in SPCA-1 NSCLC cells was significantly increased when cultured on a stiff substrate compared to a soft substrate. However, the expression of phospho-YAP protein was markedly decreased after culturing on the stiff substrate. The stiff substrate promoted the growth of NSCLC cells in vitro, and an increase in the transcription levels of survivin, connective tissue growth factor (CTGF), amphiregulin, and Ki67.[20] This showed YAP regulated the growth of NSCLC cells in response to matrix stiffness. Knockdown of the Hippo mediators YAP or TAZ decreased in vitro cellular migration and transplantation of metastatic disease. Furthermore, constitutively active YAP was sufficient to drive lung tumor progression in vivo.[18] Most significantly, clinical lung cancer patient studies also show TAZ and YAP as oncogenes in lung cancer. TAZ expression was observed in 121 of the 181 (66.8%) NSCLC. Clinicopathologically, TAZ expression was significantly associated with lung adenocarcinoma (ADC) (P = 0.002), poorer differentiation (P = 0.001), p-tumor, node, metastasis stage (P = 0.001), lymph node metastasis (P = 0.032), intratumoral vascular invasion (P = 0.004), pleural invasion (P = 0.003), adjuvant chemotherapy (P = 0.044), and poorer prognosis (P = 0.002). Overall survival was significantly prolonged in TAZ negative group when compared with TAZ positive group (61.8 vs. 47.1 months; P < 0.0001), as was disease-free survival (44.3 vs. 25.1 months; P < 0.0001).[21] This study suggests that TAZ expression is a prognostic indicator of poorer survival probability for patients with resected NSCLC. Besides, YAP is thought to be a direct oncogenic target of the chromosome 11q22 amplicon and YAP amplification is detected in 23% of human cancers including lung cancer.[22] YAP was expressed in 66.3% cases and predominantly presented in the nucleus by investigating the expression of YAP in 92 cases of NSCLC tissue. The expression of YAP in NSCLC was significantly correlated with p-TNM stage (P = 0.0037) and lymph node metastasis (P = 0.0093).[17] Nuclear overexpression of YAP contributes to pulmonary ADC growth, and that high cytoplasmic expression of YAP is an independent predictor of low pathologic TNM staging and histologic grading.[23] The differential effects of YAP expression patterns in lung cancer suggest that YAP may play important roles in different pathways. These findings may lead to new perspectives on therapeutic targeting of lung cancer.


 » Implication of Large Tumor Suppressor 1/2 in Lung Cancer Top


LATS1 is a tumor suppressor in lung cancer. Overexpression of LATS1 suppresses NSCLC cell proliferation and tumor formation in nude mice.[24] In addition, knockdown of LATS1 by small interference RNA in NSCLC cells increases cell proliferation and migration.[25] Ectopic expression of LATS1 in human lung cancer cell H460 up-regulates the level of BAX proteins and induces apoptosis.[26] LATS1 homolog LATS2 is down-regulated in NSCLC cell lines. Small interfering RNA-mediated suppression of LATS2 expression resulted in augmentation of extracellular-related kinase phosphorylation in epidermal growth factor receptor (EGFR) wild-type ADC cell lines with high basal LATS2 expression, discriminatory modulation of Akt signaling between EGFR wild-type and mutant cells, and induction of p53 accumulation in AD cell lines with low baseline p53 levels.[27] LATS2 may modulate and contribute to tumor growth via different signaling pathways in lung cancers. The human LATS2 gene is located at chromosome 13q11-12, a hot spot (67%) for loss of heterozygosity in NSCLC. Mutations were tumor specific and were absent from adjacent normal tissue and healthy controls. Down-regulation of the LATS2 gene was observed in most NSCLC tumors but was not related to any mutation or polymorphism.[28]


 » Implication of Mst and Mob in Lung Cancer Top


Recent studies have revealed that MST1 and MST2 have a tumor-suppressor function in a redundant manner and were originally identified as pro-apoptotic cytoplasmic kinases important for controlling cell growth, proliferation, and apoptosis. Using recombinant eukaryotic expression vector containing human wild-type MST1 gene to transfect human NSCLC A549 cells in vitro and in vivo, results showed that MST1 overexpression inhibited cell proliferation and induced apoptosis of A549 cells, promoted YAP (Ser127) phosphorylation. Its antiproliferative effect is associated with induction of apoptosis through the promotion of the cytoplasmic localization and phosphorylation of YAP protein at Ser127 site.[29] Human MOB1 messenger RNA (mRNA) expression was significantly decreased in the tumor of lung cancer tissue compared with normal lung tissue.[30]


 » Upstream Signaling of Hippo Pathway Top


Liver kinase B1

Liver kinase B1 (LKB1), as a serine/threonine kinase and tumor suppressor, is frequently mutated and inactivated in NSCLC.[31] Inactivating mutations of LKB1 are seen more frequently in smokers, and poorly differentiated NSCLC tumors [32] and are associated with a shorter latency, more frequent metastasis, and accelerated pulmonary tumorigenesis.[33] LKB1 acts through its substrates of the microtubule affinity-regulating kinase family to regulate the localization of the polarity determinant scribble and the activity of the core Hippo kinases.[34] YAP is functionally important for the tumor suppressive effects of LKB1. YAP is initially activated by LKB1 loss in lung ADC, which upregulates ZEB2 expression and represses DNp63 transcription in a default manner.[35] YAP as a critical mediator of LKB1 may provide a novel method to treat LKB1-related lung cancers by targeting YAP.

MicroRNAs

MicroRNAs are small noncoding RNAs that bind to the 3'-UTR of mRNAs, resulting in reduced protein expression of target genes. MicroRNAs have been identified that are elevated in cancer, for example, miR-21 and the miR-17-92 cluster, while other miRNA families are frequently downregulated in cancer, including the let-7 and miR-34 families.[36] Functional studies have supported the role of some miRNAs in promoting or preventing cancer development and progression.[37] A microRNA, miR-129-5p, directly represses YAP and TAZ expression, leading to the inactivation of TEAD transcription, and downregulation of Hippo downstream genes, CTGF and cyclin A.[38] MiR-135b is upregulated in highly invasive NSCLC cells and expression of MiR-135b enhances cancer cell invasive and migratory abilities in vitro and promotes cancer metastasis in vivo. MiR-135b targets multiple key components in the Hippo pathway, including LATS2, β-TrCP and NDR2, as well as LZTS1. Expression of miR-135b, LZTS1, LATS2, and nuclear TAZ predicts poor outcomes of NSCLC.[39] By conducting miRNA microarray expression profiling on normal lung versus adjacent lung cancers from transgenic mice, found that miR-136, miR-376a, and miR-31 were each prominently over-expressed in murine lung cancers. Engineered knockdown of miR-31, substantially repressed lung cancer cell growth and tumorigenicity. MiR-31 acts as an oncogenic miRNA in lung cancer by targeting specific tumor suppressors for repression. Using a bioinformatics find miR-31 targets included the tumor-suppressive genes LATS2 and PP2A regulatory subunit B alpha isoform (PPP2R2A).[40] These studies reveal that up-regulation of miR-129-5P and miR-31 and miR-135b promotes lung tumorigenesis and metastasis by implicating the Hippo signaling pathway.

Ras-association domain family 1

Ras-association domain family 1 (RASSF1A) is one of the most frequently silenced genes in human cancer.[41] Rassf1a-targeted mice were prone to spontaneous tumorigenesis in advanced age (18–20 months).[42] RASSF1A is a potential tumor suppressor gene that undergoes epigenetic inactivation in lung cancer through hypermethylation of its promoter region.[43] Epigenetic inactivation of isoform A (RASSF1A) was observed in 40% of primary nonsmall cell lung carcinomas.[44] RASSF1A has been identified as a critical upstream regulator of the Hippo pathway.[45] MST1 is a phylogenetically conserved partner of RASSF polypeptide family.[46] RASSF1A and WW45 (the human ortholog of Sav) activate MST2 by promoting MST2 autophosphorylation and LATS1 phosphorylation. The complex of RASSF1A, MST2, WW45, and LATS1 consists of several tumor suppressors, is conserved in mamalian cells, and appears to be involved in controlling mitotic exit.[47] LATS1 forms part of an ATR-mediated response to replication stress that requires the tumor suppressor RASSF1A. Importantly, perturbation of the ATR–RASSF1A–LATS1 signaling axis leads to genomic defects associated with loss of BRCA2 function and contributes to genomic instability and “BRCA-ness” in lung cancers.[48] These studies showed that regulation of the Hippo pathway by RASSF1A may be important in regulating apoptosis and tumorigenesis during lung cancer.

Vestigial-like 4 and angiomotin

Vestigial-like (VGLL) proteins have recently been showed as a new group of TEAD-interacting partners implicating in tumorigenesis. Different from other members in VGLL family, VGLL4 contains an extra TDU domain and is considered to be functionally different.[49] VGLL4 directly competes with YAP in binding to TEADs and executes its growth-inhibitory function through two TDU domains. VGLL4 as a novel tumor suppressor in lung carcinogenesis through negatively regulating the formation of YAP-TEAD complex, the core component of Hippo pathway.[50] Scaffold proteins angiomotin (AMOT) and angiomotin-related AMOTL1 and AMOTL2 were recently identified as negative regulators of YAP and TAZ by preventing their nuclear translocation.[51] The AMOT family proteins strongly interact with YAP WW domains through their PPXY motifs and play an important role in YAP inhibition under physiological conditions.[52] Knockdown of AMOT in a low metastatic CL1-0 lung cancer cell line initiated cancer proliferation, migration, invasion and epithelial–mesenchymal transition. The trigger of cancer progression caused by AMOT loss was transduced by decreased cytoplasmic sequestration and increased nuclear translocation of oncogenic co-activators YAP/TAZ, leading to increased expression of the growth factor, Cyr61.[53]


 » Downstream Signaling of Hippo Pathway Top


LATS2 can inhibit lung cancer cell growth through down-regulating cell cycle regulator scyclinE/CDK2 kinase activity.[54] In addition to, LATS2 was found to negatively regulate nuclear factor-kappa B signaling in NSCLC cells. Down-regulation of LATS2 was very important in the progression of NSCLC.[55] LATS2 induces apoptosis through down-regulating anti-apoptotic proteins, BCL-2 and BCL-xL, in human lung cancer cells.[56] Moreover, it has been revealed that LAST1 suppresses genomic instability by suppressing Cdk2-induced inhibition of BRCA2.[48] Thyroid transcription factor 1 (TTF1) is a homeobox-containing transcriptional factor for the development of lung ADCs.[57] TAZ binds to TTF-1, increasing the transcriptional activity of TTF-1 on the SP-C promoter and activate downstream targets such as surfactant protein C in lung epithelial cells.[58] TAZ/YAP transcriptional targets may include AXL, Cyr61, AREG, and EPR, and they are thought to implicate in TAZ/YAP-induced lung tumorigenesis and metastasis.[59] However, no single downstream gene seems attribute to TAZ/YAP-induced tumorigenic phenotypes. TAZ/YAP may activate different downstream targets in different lung cancer cell lines.


 » Targeting the Hippo Pathway for Drug Development Top


Recently, many studies have suggested that

the Hippo pathway and its effectors, the YAP/TAZ-TEAD transcription complex may be potential targets for anticancer. A screening of >3300 drugs by Pan et al. led to the identification of the Porphyrin family, such as vertepor-fin, hematoporphyrin, and protoporphyrin IX, as YAP inhibitors.[60] Gas-coupled G protein-coupled receptor (GPCR) agonists increase LATS1/2 activity, leading to suppression of YAP and TAZ activity.[61] Dobutamine and epinephrine which are GPCR agonists, and forskolin and phosphodiesterase inhibitors can activate LATS1/2, promote YAP/TAZ phosphorylation and inhibition.[62] Dobutamine, forskolin, theophylline, and rolipram are all shown to inhibit YAP/TAZ by increasing cyclic adenosine monophosphate level and activating the PKA-LATS1/2 pathway.


 » Future Perspectives Top


The Hippo pathway is a signaling pathway that regulates cell proliferation and cell death. A significant increase in the understanding of the importance of Hippo signaling in lung cancer biology has been achieved in the past years. However, some important questions remain to be answered. For instance, what are the extracellular ligands of activating Hippo pathway? Hippo signaling has a potent effect on tumor growth, so it is obvious that it interacts with other well-known cancer-related signaling pathways such as the Akt and MAPK pathways. How does Hippo signaling interact with other cancer-related signaling pathways? In addition, underlying mechanisms resulting in YAP's nuclear accumulation in cancer cells and its resistance to proteosome degradation are still unclear. Understanding the dysregulation in specific cancer type is very important, too. Because this is necessary for choosing the appropriate targeting methods. In view of the multiple genetic and epigenetic aberrations found in solid tumors such as lung cancer, it is certainly not surprising that targeted drugs have not achieved a great therapeutic success so far as single agents. Hence, combinatorial therapeutic interventions may have a greater potential of success. This depends on establishing reliable protocols to assess the molecular status of individual tumors with respect to the pathways that are being targeted.

All in all, the importance of the Hippo signaling pathway in human lung cancer has been gradually revealed, and these findings will facilitate the development of new therapeutics for treating lung cancer that have become dependent on the Hippo signaling pathway for growth.

 
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