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Role of Yes-associated Protein-1 in Gastrointestinal Cancers and Hepatocellular Carcinoma

  • Xia Qian1,#,
  • Wei Zhang1,#,
  • Hua Yang2,
  • Lanjing Zhang3,
  • Ningling Kang4 and
  • Jinping Lai5,* 
Exploratory Research and Hypothesis in Medicine   2021;6(3):110-117

doi: 10.14218/ERHM.2021.00017

Received:

Revised:

Accepted:

Published online:

 Author information

Citation: Qian X, Zhang W, Yang H, Zhang L, Kang N, Lai J. Role of Yes-associated Protein-1 in Gastrointestinal Cancers and Hepatocellular Carcinoma. Explor Res Hypothesis Med. 2021;6(3):110-117. doi: 10.14218/ERHM.2021.00017.

Abstract

Yes-associated protein-1 (YAP1) is a potent transcriptional co-activator and functions as an important downstream effector of the Hippo signaling pathway, which is key to regulating cell proliferation, apoptosis, and organ growth. YAP1 has been implicated as an oncogene for various human cancers including gastrointestinal cancers and hepatocellular carcinoma (HCC). YAP1 promotes tumorigenesis and cancer progression by multiple mechanisms, such as by promoting malignant phenotypes, expanding cancer stem cells, and inducing epithelial-mesenchymal transition. YAP1 overexpression or its activated forms are associated with advanced pathological grades and poor prognosis of cancer, and therefore targeting YAP1 may open a fertile avenue for cancer therapy. In this review, we summarize the recent evidence regarding the role of YAP1 in the carcinogenesis of gastrointestinal cancers and HCC.

Keywords

YAP1, Gastrointestinal cancers, Hepatocellular carcinomas, Carcinogenesis, Cancer therapy

Introduction

Gastrointestinal cancers involving the gastrointestinal tract and accessory organs of digestion are the most common malignancies worldwide.1 Many of these cancers have poor prognoses although the combination of surgery, endoscopic therapy, chemotherapy, and radiation may improve the survival of some patients with gastrointestinal cancers and hepatocellular carcinoma (HCC).2 The effectiveness of the treatments, however, depends on the cancer status which includes metastasis, resistance to radiation/chemotherapy, and recurrence. Given the high prevalence and mortality threat of these malignancies, further studies are needed to define prognostic, survival, and diagnostic markers for these cancers.

The Hippo signaling pathway is a critical regulator of cell proliferation, growth, and apoptosis. This pathway also provides important roles in tissue homeostasis, organ size and stem cell function.3,4 Yes-associated protein-1 (YAP1) functions as an important downstream effector of the Hippo signaling pathway and is a potent transcriptional co-activator that interacts with multiple transcription factors, such as TEA domain (TEAD) and SMAD family members, to regulate the expression of target genes.5,6 When the Hippo pathway is “on”, YAP1 is phosphorylated on serine residues and retained in the cytoplasm, limiting its co-activator function in the nucleus. In contrast, when the Hippo pathway is “off,” YAP1 translocates into the nucleus where it induces the expression of genes, such as Survivin, CTGF, JAG1, and CYR61, to promote the migration and proliferation of cancer cells (Fig. 1).7,8 Elevated nuclear YAP1 has been detected in many cancers and the overexpression of YAP1 is associated with poor prognoses for gastrointestinal cancers such as esophageal cancer (EC), gastric cancer (GC), colorectal cancer (CRC), and HCC.9 Pre-clinical studies have demonstrated that YAP1 inhibition led to the suppression of tumor progression and sensitized chemotherapy.9,10 YAP1 also plays an important role in tumor immunity, which affects tumor progression, tumor prognosis and treatment response. YAP1 expression in T cells, myeloid-derived suppressor cells, and macrophages regulates the interaction between immune and tumor cells in the tumor microenvironment.11 Therefore, YAP1 represents a potential target for anti-cancer therapy. In this review, we summarize the recent advances supporting the role of YAP1 in carcinogenesis of gastrointestinal cancers and HCC.

The Hippo-Yes-Associated Protein-1 (YAP1) pathway.
Fig. 1  The Hippo-Yes-Associated Protein-1 (YAP1) pathway.

When the Hippo pathway is “on”, YAP1 is phosphorylated and retained in the cytoplasm or degraded. When the Hippo pathway is “off,” YAP1 translocates into the nucleus where it serves as a transcription co-regulator of TEA-Domain (TEAD), induces the expression of genes such as Survivin, Connective Tissue Growth Factor (CTGF), Jagged Canonical Notch Ligand 1 (JAG1), and Cysteine-rich angiogenic inducer 61 (CYR61), thus promoting the migration and proliferation of cancer cells.

YAP1 in gastric cancer

Gastric cancer (GC) is the fifth most common and the third most life-threatening cancer worldwide. The risk factors of GC include infections with Helicobacter pylori (H. pylori) and Epstein-Barr virus (EBV), smoking, chronic atrophic gastritis, intestinal metaplasia, and genetic mutations. In the last several years, a set of tumor suppressor genes and microRNAs (miR) were identified as having expression patterns associated with different GC stages and subtypes.12,13 These genes were considered prognostic biomarkers and may serve as potential drug targets for interventional therapy. Among them, the genes encoding the Hippo-YAP1 signaling pathway emerged as important regulators for tumor formation and progression.

Clinical studies demonstrated that YAP1 overexpression in GC was related to high pathological grades, disorganized cellular differentiation, and a poor prognosis. In vitro, the inhibition of YAP1 suppressed cancer cell growth, migration, and invasion.14 Studies in mice revealed that YAP1 mediated gastric adenocarcinoma peritoneal metastasis by promoting cancer stem cell (CSC) properties, and that inhibition of YAP1 significantly decreased the CSC properties and inhibited tumor growth in this aggressive phenotype.14 With the oncogenic role of YAP1 revealed, molecular mechanisms by which YAP1 promotes GC have received attention and much progress has been made, as described below.

YAP1 promotes expression of various genes such as MYC, CTGF and AXL. It has been shown that deregulated MYC causes cell transformation and tumor progression,15 and that MYC activation affects early-stage gastric carcinogenesis.16 Additionally, MYC is a direct downstream mediator of YAP1,17 which also regulates the initiation of gastric carcinogenesis by upregulating MYC.18 YAP1 also promotes activation of the RAF/MEK/ERK pathway to enhance the expression of c-Fos in GC.19 The overexpression of YAP1 in GC is also positively correlated with survivin expression, a known inhibitor of apoptosis.20 Moreover, YAP1 interacts with RUNX2, a Runt box domain DNA-binding transcription factor, to promote oncogenic transformation through repressing the expression of p21.21 However, RUNX3, an important tumor suppressor, reduces YAP1 activity by decreasing the DNA-binding capacity of TEAD.22 Furthermore, YAP1 directly promotes SOX9 transcription by interacting with TEAD proteins at the SOX9 promoter, which induces CSC properties in non-transformed cells of gastrointestinal origin. Oncogenic and CSC properties are also promoted by the peroxisome proliferator-activated receptors δ (PPARD) in GC cell lines in which PPARD forms a complex with YAP1. PPARD directly binds the YAP1 C-terminal transactivation domain, which then promotes SOX9 transcription. Inhibition of YAP1 significantly prohibited PPARD-induced oncogenic and CSC properties in GC.23

In terms of the regulation of YAP1, it has been reported that some miRNAs, such as miR15a, miR16-1 and miR375, negatively regulate YAP1 expression.24,25 Deregulated function of these tumor suppressive miRNAs leads to YAP1 upregulation and subsequent tumorigenesis. In addition, VGLL4, a member of the Vestigial-like proteins, which directly interacts with TEAD through competing with YAP1 for binding TEADs, inhibits EMT in GC via suppressing the Wnt/β-catenin signaling pathway. A peptide mimicking VGLL4, and acting as a YAP1 antagonist, dramatically suppressed tumor formation, which suggests that inhibition of the YAP-TEADs interaction by this small molecule is a potential therapeutic method for GC.26,27

YAP1 in EC

EC has high incidence and is one of the most fatal malignancies worldwide. Targeted gene therapy is a promising prospect for improving the outcomes of EC.28 Thus, it is crucial to find therapeutic target genes for the treatment of EC.

In EC, overexpression of YAP1 has been reported in both esophageal adenocarcinoma (EAC) and squamous cell carcinoma (SCC).29,30 Recently, we also found increased expression of YAP1 in EAC, perineural invasion (N) and lymphovascular invasion (LVI) (Fig. 2). Studies have shown that the expression level of YAP1 is correlated with EC progression and that the knockdown of YAP1 suppresses esophageal tumor growth and metastasis in mice.31 The role of YAP1 in esophageal carcinogenesis and metastasis is mediated by cooperation with multiple factors. YAP1 upregulates the expression of EGFR through binding to a TEAD-binding site at the EGFR promoter in EC cells. YAP1 also promotes sustained EGFR overexpression to increase cell proliferation and confer resistance in therapy. Verteporfin (VP), a small molecular YAP1 inhibitor, significantly decreases the expression of YAP1 and EGFR, and sensitizes esophageal cancer cells to 5-fluorouracil and docetaxcel.32 YAP1 also directly promotes SOX9 transcription to confer EC cells with CSC properties including tumorsphere formation, propagation, and tumorigenicity. The YAP1 inhibitor, VP, suppresses SOX9 expression, CSC phenotypes and tumor growth.33 Moreover, YAP1 mediates histone demethylase Jumonji Domain Containing 1C (JMJD1C)-induced EC growth. JMJD1C, which is upregulated in EC, enhances the transcription of YAP1 by its activity on H3K9me2.34

YAP1 immuno-reactivity in a case of esophageal adenocarcinoma.
Fig. 2  YAP1 immuno-reactivity in a case of esophageal adenocarcinoma.

(a) YAP1 is negative in the adjacent benign esophageal columnar epithelium; b–d: YAP1 is positive in the adenocarcinoma and the carcinoma with perineural invasion (N) and lympho-vascular invasion (LVI) (a–d, 400×).

YAP1 represents a novel therapeutic target for EC with high YAP1 expression; however, targeting YAP1 in the clinical setting remains challenging. VP is the first small molecule identified as an inhibitor that targets YAP1/TEAD association and oncogenic activity of YAP1. Song et al. reported recently that the bromodomain-containing protein 4 (BRD4), a chromatin remodeling protein, significantly promotes YAP1 transcription through binding to its promoter. This work also found that the BRD4 inhibitor JQ1 effectively decreased the expression of YAP1 and YAP1 transcriptional targets (CTGF, SOX9, and Cyr61) in EAC cells. JQ1 represents a new YAP1 inhibitor, mainly targeting YAP1, which is a prevalent and therapeutic resistant tumor cell with CSC properties.35

YAP1 in PC

Pancreatic cancer (PC) is one of the most common gastrointestinal cancers and is projected to be the second most life-threatening cancer globally by 2030.36 Although many new clinical techniques have been used for the treatment of PC, the prognosis remains unsatisfactory due to limited clinical significance of the therapeutic targets.37 This makes it crucial to identify more promising therapeutic targets for PC treatment.

KRAS is a crucial oncogene for PC initiation and progression. YAP1 replaces the function of KRAS in KRAS-mutant PC cells.38 YAP1 depletion abolishes PC development that is driven by oncogenic KRAS.39,40 YAP1 activation enables the bypass of KRAS dependency to maintain PC growth.41 These insights strengthen the notion that YAP1 maintains its oncogenic roles through a pathway-independent mechanism of KRAS. Recent studies have shown that WNT5A, a prototypical non-canonical WNT ligand, enhances tumor proliferation and recurrence in a YAP1-dependent manner, which enables the bypass of KRAS dependency.42 KRAS facilitates acinar-to-ductal metaplasia and thereby generates cells for tumor initiation. This involves YAP1 activation in acinar cells and YAP1-induced transcription of genes in the JAK-STAT3 signaling pathway, leading to the development of pancreatic ductal adenocarcinoma, as seen in mice.39

PC is characterized by frequent metastasis, in which the ZEB1, a zinc-dependent EMT transcriptional factor, plays a crucial role. A recent study demonstrated that YAP1 formed a complex with ZEB1 to activate integrin alpha3 (ITGA3) transcription in human PC cells. Furthermore, the cancer-promoting zinc transporter (ZIP4) induces PC cell adhesion to ECM, EMT plasticity and metastasis through a ZEB1/YAP1-ITGA3 signaling axis.43

Increasing clinical data also shows that YAP1 is overexpressed in PC and its high expression is correlated with poor patient survival. This implies that inhibiting nuclear accumulation of YAP1 is a potential therapeutic strategy to manage PC. The combination of metformin and LW6 significantly inhibits PC cell proliferation, migration, and viability via increased YAP1 phosphorylation and reduced nuclear localization of YAP1.44 In addition, miR141 and miR375 have been reported to negatively regulate YAP1 in PC, thereby inhibiting cancer cell growth.45,46

YAP1 in CRC

CRC remains the third most common cancer and the second most life-threatening cancer worldwide. Many studies have reported increased YAP1 expression in CRC, with the activation of YAP1 being correlated with poor prognosis of CRC.47–49 Wang et al. proved the association between high YAP1 expression and shorter patient survival, and a positive association of high YAP1 expression with TNM stage.50 Immunohistochemistry showed that nuclear YAP1 level is positively correlated with the expression of Ki67 and phosphorylated ERK, which induces CRC cell growth and progression.51 In CRC samples, the activated YAP1 level is positively correlated with the expression level of EMT markers, including vimentin and N-cadherin, as well as EMT-inducing transcription factors, including Snail1, Slug and zinc finger E-box binding homeobox 1 and 2.52 Recent studies have revealed a novel role of YAP1 in regulating non-coding RNAs (ncRNAs) in CRC, including microRNAs (miR130a and miR29) and long non-coding RNAs (lncRNAs) (RMRP, BCAR4, MALAT1, and lncARSR). LINC00152 is one of the known YAP1 target IncRNAs, which is highly expressed in human CRC tissues and induces CRC cell proliferation, invasion, and metastasis.53 In addition, YAP1 exhibits cross-talk with the Wnt/β-catenin signaling pathway, which plays an important role in CSC self-renewal and tumorigenesis in CRC.54

YAP1 has also been reported to be upregulated in 5-Flourouracil (5FU)-resistant cancer cells and correlated with colon cancer relapse.55 YAP1 activation is also correlated with resistance to cetuximab therapy, and only patients without YAP1 activation benefited from cetuximab treatment.56

In CRC, YAP1 transcription is positively regulated by β-catenin, HIF1α, NFkB, TEAD or CREB.57 Inactivation of tumor suppressor adenomatous polyposis coli (APC) initiates carcinogenesis of CRC through activating β-catenin. A recent study reported that APC inactivation leads to up-regulation of interleukin 6 (IL6) signal transducer (IL6ST/gp130), thereby activating Src family kinases (SFKs), which induce nuclear activation of YAP1 in human CRC cells. On the other hand, activated YAP1 promotes IL6ST transcription. This YAP1-IL6ST auto-regulatory loop, which is induced by APC inactivation, has been shown to regulate CRC tumorigenesis.58

YAP1 in HCC

HCC is the sixth most frequent cancer and the third leading cause of cancer-related death globally.59 The majority of HCC cases present at advanced stages due to most patients with underlying chronic liver disease or cirrhosis. Despite recent improvement in the treatment methods for advanced HCC, the prognosis remains unsatisfactory.

Overexpression of YAP1 in HCC is reported to be correlated with advanced pathological grades, poor prognosis and chemoresistance.60 Xu et al. reported that YAP1 can serve as an independent prognostic marker for HCC, and that increased YAP1 expression is associated with decreased survival.61 It is reported that in transgenic mice with YAP1 overexpression, the liver size is expanded and ultimately progresses to HCC, which implies a vital role of YAP1 in hepatocarcinogenesis.62,63 As a transcriptional co-activator, YAP1 is involved in several important tumorigenic signaling pathways in HCC. YAP1 up-regulates Jagged-1 to activate Notch signaling for an oncogenic effect.64 YAP1 also regulates PI3K-mTOR pathways via suppressing PTEN.65 YAP1 activates the AKT/mTOR, ERK/MAPK and Notch pathways through concomitant action with PI3K for carcinogenesis in the liver.66 CSCs have been reported to be responsible for chemoresistance and the recurrence of HCC.67,68 YAP1 has been reported to be expressed concurrently with two stem cell markers, EPCAM and keratin 19, in HCC.69 Microarray-based transcriptome data showed that YAP1 promoted liver CSCs self-renewal activity via regulating long ncRNAs expression.70 Additional work demonstrates that the adriamycin treatment significantly amplified the oncogenic effects of YAP1, and that YAP1 induced the expression of various stem-cell markers and ATP-binding cassette transporters in adriamycin-resistant HCC cells. Moreover, miR590-5p decreases HCC chemoresistance through modulating YAP1 expression, and YAP1 is dramatically upregulated in the residual/recurrent HCC after transarterial chemoembolization (TACE) treatment.70 In addition, we also found that YAP1 expression was weakly positive in the primary HCC but was significantly increased in the residual HCC after TACE treatment (Fig. 3).

YAP1 immuno-reactivity in a case of primary hepatocellular carcinoma (HCC) (a, b) and the residual HCC after trans-arterial chemoembolization (TACE) treatment (c, d) with background of TACE-caused tumor necrosis (N) (a and c, H&E stain; a, 400×; c, 100×;) YAP1 is weakly positive in the primary HCC (b) but increased expression in the residual HCC (d) (b–d, YAP IHC, 400×).
Fig. 3  YAP1 immuno-reactivity in a case of primary hepatocellular carcinoma (HCC) (a, b) and the residual HCC after trans-arterial chemoembolization (TACE) treatment (c, d) with background of TACE-caused tumor necrosis (N) (a and c, H&E stain; a, 400×; c, 100×;) YAP1 is weakly positive in the primary HCC (b) but increased expression in the residual HCC (d) (b–d, YAP IHC, 400×).

In recent years, different immunotherapies have been used to treat HCC.71 YAP1 has been reported to play important roles in tumor cell immune escape. YAP1 contributes to the immune escape by directly binding to the enhancer to induce PD-L1 expression.72 In HCC, the expression of YAP1 in peripheral blood mononuclear cells is positively associated with the enrichment of regulatory T cells in the tumor tissue, and is negatively associated with patient survival.73 YAP1 exerts this effect by directly promoting TGFBR2 transcription. YAP1 also facilitates the recruitment of M2 macrophages via activating the release of the chemokines CCL2 and CSF1 for liver tumorigenesis.74 YAP1 also upregulates CCL2 expression in hepatocytes to induce macrophage infiltration and promote HCC development.75 A recent study also showed that through regulating monocyte chemotactic protein 1 (Mcp1), the activated YAP1 promotes macrophage infiltration, which impairs immune clearance of transforms hepatocytes, leading to HCC development.76

YAP1 is also overexpressed in other hepatic malignancies, such as hepatoblastoma (HB) and cholangiocarcinoma (CCA).77 We also found high expression of YAP1 in the hepatoblastoma, especially in the embryonal component (Fig. 4). YAP1 interacts with β-catenin in hepatoblastoma, which is increased in most human hepatoblatomas. Overexpression of the activated forms of YAP1 and β-catenin in hepatocytes also promotes rapid tumor development.78 Pei et al. reports that the nuclear YAP1 level is positively correlated with TNM stage and poor prognosis of CCA. YAP1 induces EMT and promotes the progression of CCA through forming a regulatory circuit with miR29c, IGF1, AKT and gankyrin.79

YAP1 immuno-reactivity in a case of hepatoblastoma (HB).
Fig. 4  YAP1 immuno-reactivity in a case of hepatoblastoma (HB).

(a) Histology of HB with fetal (left) and embryonal (right) components in the background of osteoid; (b) YAP1 is weakly positive in the fetal component (left) and increased expression in the embryonal component (right) (a, H&E stain; 200×; b, YAP1, 400×).

YAP1 is also correlated with situations pre-disposed to HCC development, such as nonalcoholic fatty liver disease (NAFLD). YAP1 activation increases the insulin receptor substrate IRS2, which subsequently leads to AKT activation and disease progression of NAFLD, and eventually HCC.80 It has also been reported that the long non-coding RNA lncARSR activates the IRS2/AKT signaling pathway by binding to YAP1 and that this binding inhibits YAP1 phosphorylation and promotes YAP1 nuclear translocation, which in turn accelerates NAFLD progression.81

Future directions

YAP1 functions as an important downstream effector of the Hippo signaling pathway and is a potent transcriptional co-activator that interacts with multiple transcription factors to regulate the expression of target genes. When the Hippo pathway is “on”, YAP1 is phosphorylated on serine residues and retained in the cytoplasm, limiting its co-activator function in the nucleus. In contrast, when the Hippo pathway is “off,” YAP1 translocates into the nucleus where it induces the expression of genes to promote the migration and proliferation of cancer cells. Elevated nuclear YAP1 has been detected in many cancers and the overexpression of YAP1 is associated with poor prognoses for gastrointestinal cancers and HCC. We hypothesize that YAP1 may serve as a treatment target for some gastrointestinal and liver cancers.

Conclusions

In conclusion, accumulating evidence reveals that YAP1 plays a crucial role in tumorigenesis, metastasis and chemoresistance in gastrointestinal cancer and HCC. This support strengthens the notion that YAP1 is a potential therapeutic target; however, further studies are required to explore novel transcription factors that mediate the function of YAP1 and additional regulatory mechanisms of YAP1 in cancer cells. These studies will greatly advance our understanding of the role of YAP1 in carcinogenesis.

Abbreviations

APC: 

Adenomatous Polyposis Coli

BRD4: 

Bromodomain-Containing Protein 4

CCA: 

cholangiocarcinoma

CCL2: 

C-C Motif Chemokine Ligand 2

CRC: 

Colorectal Cancer

CREB: 

cAMP-response element binding protein

CSF1: 

Colony Stimulating Factor 1

CTGF: 

Connective Tissue Growth Factor

CYR61: 

Cysteine-rich angiogenic inducer 61

EAC: 

Esophageal Adenocarcinoma

EC: 

Esophageal Cancer

ECM: 

Extracellular Matrix

EMT: 

Epithelial-Mesenchymal Transition

EPCAM: 

Epithelial cell adhesion molecule

ERK: 

Extracellular Signal-Regulated Kinase

5-FU: 

5-Fluorouracil

H3K9me2: 

Histone H3K9 Dimethylation

HB: 

hepatoblastoma

HCC: 

Hepatocellular Carcinoma

HIF1a: 

Hypoxia Inducible Factor 1 Subunit Alpha

IGF1: 

Insulin Growth Factor 1

IL: 

Interleukin

IRS2: 

Insulin Related Substrate 2

ITGA: 

Integrin Subunit Alpha

ITGA3: 

Integrin A 3

JAG1: 

Jagged Canonical Notch Ligand 1

JAK-STAT: 

Janus Kinase-Signal Transducer and Activator of Transcription

JMJD1C: 

Jumonji Domain-Containing Protein 1C

lncRNA: 

long non-coding RNA

M: 

Metastasis

MAPK: 

mitogen-activated protein kinase

Mcp1: 

monocyte chemotactic protein 1

miR: 

MicroRNA

mTOR: 

mechanistic target of rapamycin

N: 

Node

NAFLD: 

nonalcoholic fatty liver disease

ncRNAs: 

Non-coding RNAs

NFkB: 

Nuclear Factor kappa-B

nYAP: 

nuclear YAP

PDAC: 

Pancreatic Ductal Adenocarcinoma

PD-L1: 

Programmed death-ligand 1

PI3K: 

Phosphatidylinositol-3-kinase

PPARD: 

Peroxisome Proliferator Activated Receptor Delta

PPARE: 

Peroxisome Proliferator-Activated Receptor Element

PTEN: 

Phosphatase and tensin homolog

RUNX: 

Runt-related transcription factor

SCC: 

Squamous Cell Carcinoma

SOX9: 

SRY-Box Transcription Factor 9

STAT3: 

Signal Transducer and Activator of Transcription 3

T: 

Tumor

TACE: 

transarterial chemoembolization

TAZ: 

Tafazzin

TEAD: 

TEA Domain

TGFBR2: 

Transforming Growth Factor Beta Receptor 2

Tregs: 

regulatory T cells

VGLL4: 

Vestigial Like Family Member 4

VP: 

Verteporfin

YAP1: 

Yes-Associated Protein-1

ZEB1: 

Zinc Finger E-Box Binding Homeobox 1

Declarations

Acknowledgement

None.

Data sharing statement

No additional data are available.

Funding

This study was supported by NIH grant R01 CA160069 to NK.

Conflict of interest

The authors declare that they have no conflict of interest regarding this article

Authors’ contributions

XQ and WZ wrote the manuscript; HY, LZ and NK critically reviewed the manuscript; JL collected and analyzed the data and finalized the manuscript. All authors have made a significant contribution and have approved the final manuscript.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71(3):209-249 View Article PubMed/NCBI
  2. Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, et al. SEER Cancer Statistics Review, 1975-2018, National Cancer Institute. Available from: https://seer.cancer.gov/csr/1975_2018/. Accessed April, 2021 View Article PubMed/NCBI
  3. Liu H, Jiang D, Chi F, Zhao B. The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation. Protein Cell 2012;3(4):291-304 View Article PubMed/NCBI
  4. Zhao B, Li L, Lei Q, Guan KL. The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes Dev 2010;24(9):862-874 View Article PubMed/NCBI
  5. Moroishi T, Hansen CG, Guan KL. The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer 2015;15(2):73-79 View Article PubMed/NCBI
  6. Zhao B, Ye X, Yu J, Li L, Li W, Li S, et al. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev 2008;22(14):1962-1971 View Article PubMed/NCBI
  7. Liu-Chittenden Y, Huang B, Shim JS, Chen Q, Lee SJ, Anders RA, et al. Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev 2012;26(12):1300-1305 View Article PubMed/NCBI
  8. Pobbati AV, Hong W. Emerging roles of TEAD transcription factors and its coactivators in cancers. Cancer Biol Ther 2013;14(5):390-398 View Article PubMed/NCBI
  9. Shibata M, Ham K, Hoque MO. A time for YAP1: Tumorigenesis, immunosuppression and targeted therapy. Int J Cancer 2018;143(9):2133-2144 View Article PubMed/NCBI
  10. Ooki A, Del Carmen Rodriguez Pena M, Marchionni L, Dinalankara W, Begum A, Hahn NM, et al. YAP1 and COX2 Coordinately Regulate Urothelial Cancer Stem-like Cells. Cancer Res 2018;78(1):168-181 View Article PubMed/NCBI
  11. Pan Z, Tian Y, Cao C, Niu G. The Emerging Role of YAP/TAZ in Tumor Immunity. Mol Cancer Res 2019;17(9):1777-1786 View Article PubMed/NCBI
  12. Lee HS, Lee HK, Kim HS, Yang HK, Kim WH. Tumour suppressor gene expression correlates with gastric cancer prognosis. J Pathol 2003;200(1):39-46 View Article PubMed/NCBI
  13. Li X, Zhang Y, Zhang Y, Ding J, Wu K, Fan D. Survival prediction of gastric cancer by a seven-microRNA signature. Gut 2010;59(5):579-585 View Article PubMed/NCBI
  14. Ajani JA, Xu Y, Huo L, Wang R, Li Y, Wang Y, et al. YAP1 mediates gastric adenocarcinoma peritoneal metastases that are attenuated by YAP1 inhibition. Gut 2021;70(1):55-66 View Article PubMed/NCBI
  15. Chung HJ, Levens D. c-myc expression: keep the noise down!. Mol Cells 2005;20(2):157-166 View Article PubMed/NCBI
  16. Calcagno DQ, Leal MF, Assumpcao PP, Smith MA, Burbano RR. MYC and gastric adenocarcinoma carcinogenesis. World J Gastroenterol 2008;14(39):5962-5968 View Article PubMed/NCBI
  17. Croci O, De Fazio S, Biagioni F, Donato E, Caganova M, Curti L, et al. Transcriptional integration of mitogenic and mechanical signals by Myc and YAP. Genes Dev 2017;31(20):2017-2022 View Article PubMed/NCBI
  18. Choi W, Kim J, Park J, Lee DH, Hwang D, Kim JH, et al. YAP/TAZ Initiates Gastric Tumorigenesis via Upregulation of MYC. Cancer Res 2018;78(12):3306-3320 View Article PubMed/NCBI
  19. Kang W, Tong JH, Chan AW, Lee TL, Lung RW, Leung PP, et al. Yes-associated protein 1 exhibits oncogenic property in gastric cancer and its nuclear accumulation associates with poor prognosis. Clin Cancer Res 2011;17(8):2130-2139 View Article PubMed/NCBI
  20. Da CL, Xin Y, Zhao J, Luo XD. Significance and relationship between Yes-associated protein and survivin expression in gastric carcinoma and precancerous lesions. World J Gastroenterol 2009;15(32):4055-4061 View Article PubMed/NCBI
  21. Vitolo MI, Anglin IE, Mahoney WM, Renoud KJ, Gartenhaus RB, Bachman KE, et al. The RUNX2 transcription factor cooperates with the YES-associated protein, YAP65, to promote cell transformation. Cancer Biol Ther 2007;6(6):856-863 View Article PubMed/NCBI
  22. Qiao Y, Lin SJ, Chen Y, Voon DC, Zhu F, Chuang LS, et al. RUNX3 is a novel negative regulator of oncogenic TEAD-YAP complex in gastric cancer. Oncogene 2016;35(20):2664-2674 View Article PubMed/NCBI
  23. Song S, Wang Z, Li Y, Ma L, Jin J, Scott AW, et al. PPARdelta Interacts with the Hippo Coactivator YAP1 to Promote SOX9 Expression and Gastric Cancer Progression. Mol Cancer Res 2020;18(3):390-402 View Article PubMed/NCBI
  24. Kang W, Huang T, Zhou Y, Zhang J, Lung RWM, Tong JHM, et al. miR-375 is involved in Hippo pathway by targeting YAP1/TEAD4-CTGF axis in gastric carcinogenesis. Cell Death Dis 2018;9(2):92 View Article PubMed/NCBI
  25. Kang W, Tong JH, Lung RW, Dong Y, Zhao J, Liang Q, et al. Targeting of YAP1 by microRNA-15a and microRNA-16-1 exerts tumor suppressor function in gastric adenocarcinoma. Mol Cancer 2015;14:52 View Article PubMed/NCBI
  26. Jiao S, Wang H, Shi Z, Dong A, Zhang W, Song X, et al. A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer. Cancer Cell 2014;25(2):166-180 View Article PubMed/NCBI
  27. Li H, Wang Z, Zhang W, Qian K, Liao G, Xu W, et al. VGLL4 inhibits EMT in part through suppressing Wnt/beta-catenin signaling pathway in gastric cancer. Med Oncol 2015;32(3):83 View Article PubMed/NCBI
  28. Ginn SL, Alexander IE, Edelstein ML, Abedi MR, Wixon J. Gene therapy clinical trials worldwide to 2012 - an update. J Gene Med 2013;15(2):65-77 View Article PubMed/NCBI
  29. Lam-Himlin DM, Daniels JA, Gayyed MF, Dong J, Maitra A, Pan D, et al. The hippo pathway in human upper gastrointestinal dysplasia and carcinoma: a novel oncogenic pathway. Int J Gastrointest Cancer 2006;37(4):103-109 View Article PubMed/NCBI
  30. Muramatsu T, Imoto I, Matsui T, Kozaki K, Haruki S, Sudol M, et al. YAP is a candidate oncogene for esophageal squamous cell carcinoma. Carcinogenesis 2011;32(3):389-398 View Article PubMed/NCBI
  31. Zhao J, Li X, Yang Y, Zhu D, Zhang C, Liu D, et al. Effect of YAP1 silencing on esophageal cancer. Onco Targets Ther 2016;9:3137-3146 View Article PubMed/NCBI
  32. Song S, Honjo S, Jin J, Chang SS, Scott AW, Chen Q, et al. The Hippo Coactivator YAP1 Mediates EGFR Overexpression and Confers Chemoresistance in Esophageal Cancer. Clin Cancer Res 2015;21(11):2580-2590 View Article PubMed/NCBI
  33. Song S, Ajani JA, Honjo S, Maru DM, Chen Q, Scott AW, et al. Hippo coactivator YAP1 upregulates SOX9 and endows esophageal cancer cells with stem-like properties. Cancer Res 2014;74(15):4170-4182 View Article PubMed/NCBI
  34. Cai Y, Fu X, Deng Y. Histone demethylase JMJD1C regulates esophageal cancer proliferation Via YAP1 signaling. Am J Cancer Res 2017;7(1):115-124 View Article PubMed/NCBI
  35. Song S, Li Y, Xu Y, Ma L, Pool Pizzi M, Jin J, et al. Targeting Hippo coactivator YAP1 through BET bromodomain inhibition in esophageal adenocarcinoma. Mol Oncol 2020;14(6):1410-1426 View Article PubMed/NCBI
  36. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014;74(11):2913-2921 View Article PubMed/NCBI
  37. Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med 2019;381(4):317-327 View Article PubMed/NCBI
  38. Shao DD, Xue W, Krall EB, Bhutkar A, Piccioni F, Wang X, et al. KRAS and YAP1 converge to regulate EMT and tumor survival. Cell 2014;158(1):171-184 View Article PubMed/NCBI
  39. Gruber R, Panayiotou R, Nye E, Spencer-Dene B, Stamp G, Behrens A. YAP1 and TAZ Control Pancreatic Cancer Initiation in Mice by Direct Up-regulation of JAK-STAT3 Signaling. Gastroenterology 2016;151(3):526-539 View Article PubMed/NCBI
  40. Zhang W, Nandakumar N, Shi Y, Manzano M, Smith A, Graham G, et al. Downstream of mutant KRAS, the transcription regulator YAP is essential for neoplastic progression to pancreatic ductal adenocarcinoma. Sci Signal 2014;7(324):ra42 View Article PubMed/NCBI
  41. Kapoor A, Yao W, Ying H, Hua S, Liewen A, Wang Q, et al. Yap1 Activation Enables Bypass of Oncogenic Kras Addiction in Pancreatic Cancer. Cell 2019;179(5):1239 View Article PubMed/NCBI
  42. Tu B, Yao J, Ferri-Borgogno S, Zhao J, Chen S, Wang Q, et al. YAP1 oncogene is a context-specific driver for pancreatic ductal adenocarcinoma. JCI Insight 2019;4(21):e130811 View Article PubMed/NCBI
  43. Liu M, Zhang Y, Yang J, Zhan H, Zhou Z, Jiang Y, et al. Zinc-Dependent Regulation of ZEB1 and YAP1 Coactivation Promotes Epithelial-Mesenchymal Transition Plasticity and Metastasis in Pancreatic Cancer. Gastroenterology 2021;160(5):1771-1783.e1 View Article PubMed/NCBI
  44. Zhang X, Liu P, Shang Y, Kerndl H, Kumstel S, Gong P, et al. Metformin and LW6 impairs pancreatic cancer cells and reduces nuclear localization of YAP1. J Cancer 2020;11(2):479-487 View Article PubMed/NCBI
  45. Zhang ZW, Men T, Feng RC, Li YC, Zhou D, Teng CB. miR-375 inhibits proliferation of mouse pancreatic progenitor cells by targeting YAP1. Cell Physiol Biochem 2013;32(6):1808-1817 View Article PubMed/NCBI
  46. Zhu ZM, Xu YF, Su QJ, Du JD, Tan XL, Tu YL, et al. Prognostic significance of microRNA-141 expression and its tumor suppressor function in human pancreatic ductal adenocarcinoma. Mol Cell Biochem 2014;388(1-2):39-49 View Article PubMed/NCBI
  47. Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC, et al. Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. PNAS 2006;103(33):12405-12410 View Article PubMed/NCBI
  48. Steinhardt AA, Gayyed MF, Klein AP, Dong J, Maitra A, Pan D, et al. Expression of Yes-associated protein in common solid tumors. Hum Pathol 2008;39(11):1582-1589 View Article PubMed/NCBI
  49. Zhou D, Zhang Y, Wu H, Barry E, Yin Y, Lawrence E, et al. Mst1 and Mst2 protein kinases restrain intestinal stem cell proliferation and colonic tumorigenesis by inhibition of Yes-associated protein (Yap) overabundance. PNAS 2011;108(49):E1312-1320 View Article PubMed/NCBI
  50. Wang Y, Xie C, Li Q, Xu K, Wang E. Clinical and prognostic significance of Yes-associated protein in colorectal cancer. Tumour Biol 2013;34(4):2169-2174 View Article PubMed/NCBI
  51. Kim DH, Kim SH, Lee OJ, Huang SM, Kwon JL, Kim JM, et al. Differential expression of Yes-associated protein and phosphorylated Yes-associated protein is correlated with expression of Ki-67 and phospho-ERK in colorectal adenocarcinoma. Histol Histopathol 2013;28(11):1483-1490 View Article PubMed/NCBI
  52. Jiang L, Zhang J, Xu Q, Wang B, Yao Y, Sun L, et al. YAP promotes the proliferation and migration of colorectal cancer cells through the Glut3/AMPK signaling pathway. Oncol Lett 2021;21(4):312 View Article PubMed/NCBI
  53. Ou C, Sun Z, He X, Li X, Fan S, Zheng X, et al. Targeting YAP1/LINC00152/FSCN1 Signaling Axis Prevents the Progression of Colorectal Cancer. Adv Sci (Weinh) 2020;7(3):1901380 View Article PubMed/NCBI
  54. Zhang K, Qi HX, Hu ZM, Chang YN, Shi ZM, Han XH, et al. YAP and TAZ Take Center Stage in Cancer. Biochemistry 2015;54(43):6555-6566 View Article PubMed/NCBI
  55. Touil Y, Igoudjil W, Corvaisier M, Dessein AF, Vandomme J, Monté D, et al. Colon cancer cells escape 5FU chemotherapy-induced cell death by entering stemness and quiescence associated with the c-Yes/YAP axis. Clin Cancer Res 2014;20(4):837-846 View Article PubMed/NCBI
  56. Lee KW, Lee SS, Kim SB, Sohn BH, Lee HS, Jang HJ, et al. Significant association of oncogene YAP1 with poor prognosis and cetuximab resistance in colorectal cancer patients. Clin Cancer Res 2015;21(2):357-364 View Article PubMed/NCBI
  57. Mouillet-Richard S, Laurent-Puig P. YAP/TAZ Signalling in Colorectal Cancer: Lessons from Consensus Molecular Subtypes. Cancers (Basel) 2020;12(11):3160 View Article PubMed/NCBI
  58. Taniguchi K, Moroishi T, de Jong PR, Krawczyk M, Grebbin BM, Luo H, et al. YAP-IL-6ST autoregulatory loop activated on APC loss controls colonic tumorigenesis. PNAS 2017;114(7):1643-1648 View Article PubMed/NCBI
  59. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin 2020;70(1):7-30 View Article PubMed/NCBI
  60. Han SX, Bai E, Jin GH, He CC, Guo XJ, Wang LJ, et al. Expression and clinical significance of YAP, TAZ, and AREG in hepatocellular carcinoma. J Immunol Res 2014;2014:261365 View Article PubMed/NCBI
  61. Xu MZ, Yao TJ, Lee NP, Ng IO, Chan YT, Zender L, et al. Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma. Cancer 2009;115(19):4576-4585 View Article PubMed/NCBI
  62. Li S, Han Z, Ma Y, Song R, Pei T, Zheng T, et al. Hydroxytyrosol inhibits cholangiocarcinoma tumor growth: an in vivo and in vitro study. Oncol Rep 2014;31(1):145-152 View Article PubMed/NCBI
  63. Zhou D, Conrad C, Xia F, Park JS, Payer B, Yin Y, et al. Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell 2009;16(5):425-438 View Article PubMed/NCBI
  64. Tschaharganeh DF, Chen X, Latzko P, Malz M, Gaida MM, Felix K, et al. Yes-associated protein up-regulates Jagged-1 and activates the Notch pathway in human hepatocellular carcinoma. Gastroenterology 2013;144(7):1530-1542.e12 View Article PubMed/NCBI
  65. Tumaneng K, Schlegelmilch K, Russell RC, Yimlamai D, Basnet H, Mahadevan N, et al. YAP mediates crosstalk between the Hippo and PI(3)K-TOR pathways by suppressing PTEN via miR-29. Nat Cell Biol 2012;14(12):1322-1329 View Article PubMed/NCBI
  66. Li X, Tao J, Cigliano A, Sini M, Calderaro J, Azoulay D, et al. Co-activation of PIK3CA and Yap promotes development of hepatocellular and cholangiocellular tumors in mouse and human liver. Oncotarget 2015;6(12):10102-10115 View Article PubMed/NCBI
  67. Schulte LA, Lopez-Gil JC, Sainz B, Hermann PC. The Cancer Stem Cell in Hepatocellular Carcinoma. Cancers (Basel) 2020;12(3):684 View Article PubMed/NCBI
  68. Zeng Z, Ren J, O’Neil M, Zhao J, Bridges B, Cox J, et al. Impact of stem cell marker expression on recurrence of TACE-treated hepatocellular carcinoma post liver transplantation. BMC Cancer 2012;12:584 View Article PubMed/NCBI
  69. Kim GJ, Kim H, Park YN. Increased expression of Yes-associated protein 1 in hepatocellular carcinoma with stemness and combined hepatocellular-cholangiocarcinoma. PLoS One 2013;8(9):e75449 View Article PubMed/NCBI
  70. Zhu P, Wang Y, Wu J, Huang G, Liu B, Ye B, et al. LncBRM initiates YAP1 signalling activation to drive self-renewal of liver cancer stem cells. Nat Commun 2016;7:13608 View Article PubMed/NCBI
  71. Prieto J, Melero I, Sangro B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2015;12(12):681-700 View Article PubMed/NCBI
  72. Miao J, Hsu PC, Yang YL, Xu Z, Dai Y, Wang Y, et al. YAP regulates PD-L1 expression in human NSCLC cells. Oncotarget 2017;8(70):114576-114587 View Article PubMed/NCBI
  73. Fan Y, Gao Y, Rao J, Wang K, Zhang F, Zhang C. YAP-1 Promotes Tregs Differentiation in Hepatocellular Carcinoma by Enhancing TGFBR2 Transcription. Cell Physiol Biochem 2017;41(3):1189-1198 View Article PubMed/NCBI
  74. Guo X, Zhao Y, Yan H, Yang Y, Shen S, Dai X, et al. Single tumor-initiating cells evade immune clearance by recruiting type II macrophages. Genes Dev 2017;31(3):247-259 View Article PubMed/NCBI
  75. Kim W, Khan SK, Liu Y, Xu R, Park O, He Y, et al. Hepatic Hippo signaling inhibits protumoural microenvironment to suppress hepatocellular carcinoma. Gut 2018;67(9):1692-1703 View Article PubMed/NCBI
  76. Manmadhan S, Ehmer U. Hippo Signaling in the Liver - A Long and Ever-Expanding Story. Front Cell Dev Biol 2019;7:33 View Article PubMed/NCBI
  77. Li H, Wolfe A, Septer S, Edwards G, Zhong X, Abdulkarim AB, et al. Deregulation of Hippo kinase signalling in human hepatic malignancies. Liver Int 2012;32(1):38-47 View Article PubMed/NCBI
  78. Chen M, Wu L, Tu J, Zhao Z, Fan X, Mao J, et al. miR-590-5p suppresses hepatocellular carcinoma chemoresistance by targeting YAP1 expression. EBioMedicine 2018;35:142-154 View Article PubMed/NCBI
  79. Pei T, Li Y, Wang J, Wang H, Liang Y, Shi H, et al. YAP is a critical oncogene in human cholangiocarcinoma. Oncotarget 2015;6(19):17206-17220 View Article PubMed/NCBI
  80. Jeong SH, Kim HB, Kim MC, Lee JM, Lee JH, Kim JH, et al. Hippo-mediated suppression of IRS2/AKT signaling prevents hepatic steatosis and liver cancer. J Clin Invest 2018;128(3):1010-1025 View Article PubMed/NCBI
  81. Chi Y, Gong Z, Xin H, Wang Z, Liu Z. Long noncoding RNA lncARSR promotes nonalcoholic fatty liver disease and hepatocellular carcinoma by promoting YAP1 and activating the IRS2/AKT pathway. J Transl Med 2020;18(1):126 View Article PubMed/NCBI

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