Role of Hippo pathway dysregulation from gastrointestinal premalignant lesions to cancer

Abstract

Background: First identified in Drosophila melanogaster, the Hippo pathway is considered a major regulatory cascade controlling tissue homeostasis and organ development. Hippo signaling components include kinases whose activity regulates YAP and TAZ final effectors. In response to upstream stimuli, YAP and TAZ control transcriptional programs involved in cell proliferation, cytoskeletal reorganization and stemness.

Main text: While fine tuning of Hippo cascade components is essential for maintaining the balance between proliferative and non-proliferative signals, pathway signaling is frequently dysregulated in gastrointestinal cancers. Also, YAP/TAZ aberrant activation has been described in conditions characterized by chronic inflammation that precede cancer development, suggesting a role of Hippo effectors in triggering carcinogenesis. In this review, we summarize the architecture of the Hippo pathway and discuss the involvement of signaling cascade unbalances in premalignant lesions of the gastrointestinal tract, providing a focus on the underlying molecular mechanisms.

Conclusions: The biology of premalignant Hippo signaling dysregulation needs further investigation in order to elucidate the evolutionary trajectories triggering cancer inititation and develop effective early therapeutic strategies targeting the Hippo/YAP pathway.

Keywords: Chronic inflammation; Fibrosis; Gastrointestinal tumors; Hippo pathway; Precancerous lesions; YAP/TAZ.

Fig. 1

Hippo signaling pathway and its network. When upstream signals activate the Hippo pathway (Hippo ON), the phosphorylation cascade is enabled that ultimately induces YAP/TAZ proteasomal degradation (leftside). In Hippo OFF conformation, promoted by mechanical signaling and hormones, YAP/TAZ can translocate to the nucleus. Here, by interacting with TEAD transcription factors and cofactors, YAP/TAZ activate the transcription of target genes. ABCP: apico-basal cell polarity protein; AMOT: angiomotin; AMPK: AMP-activated protein kinase; AREG: amphiregulin; CTGF: connective tissue growth factor; CRB: crumbs; CYR61: Cysteine-rich angiogenic inducer 61; KIBRA: kidney and brain expressed protein; NF2: neurofibromin 2; RUNX2: Runt-related transcription factor 2; SCD1: Stearoyl-CoA-desaturase-1; SMAD: small mother against decapentaplegic; TAO: thousand-and-one amino acid

Fig. 2

Hippo pathway dysregulation from liver precursor lesions to malignancy. Mechanisms contributing to YAP/TAZ aberrant activation in hepatic precancerous lesions (HBV infection, NAFLD/NASH/ASH and liver fibrosis). ANKRD11: cardiac ankyrin repeat protein; ASH: alcoholic steatohepatitis; BMI1: B lymphoma Mo-MLV insertion region 1 homolog; CREBP: cAMP response element-binding protein; CXCL1: CXC motif chemokine ligand 1; CYR61: cysteine-rich angiogenic inducer 61; FKBP5: FK506-binding protein 51;HBsAg: HBV surface antigen; HBV: hepatitis B virus; HBx: hepatitis B virus X protein; HCC: hepatocellular carcinoma; IHH: Indian hedgehog; JCAD: junctional cadherin 5 associated; LATS1: large tumor suppressor 1; MST1/2: serine/threonine kinases sterile 20-like kinase 1 and 2; NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; NOTCH: neurogenic locus notch homolog protein; TAZ: Transcriptional co-activator with PDZ-binding domainTEAD: TEA domain-containing sequence-specific transcription factors; TGF-β: transforming growth factor beta; YAP: Yes-associated protein

Fig. 3

Hippo pathway dysregulation from esophageal precursor lesions to malignancy. Mechanisms contributing to dysfunctional Hippo signaling from normal to neoplastic esophagus across gastroesophageal reflux disease-Barrett esophagus/dysplasia. APE1: apurinic/apyrimidinic endonuclease 1; CSC: cancer stem cell; LOH: loss of heterozygosity; S1PR2: sphingosine 1-phosphate receptor 2; β-TRCP: β-transducin repeat-containing protein; YAP: Yes-associated protein

Fig. 4

Hippo pathway dysregulation from pancreas precursor lesions to malignancy. YAP/TAZ aberrant activation is an early event in sporadic and hereditary pancreatitis, pancreatic intraepithelial neoplasia, mucinous cystic lesions and intraductal tubulopapillary neoplasm. ADM: acinar-to ductal metaplasia; CP: chronic pancreatitis; GNAS: guanine nucleotide binding protein, alpha stimulating;IPMN: intraductal papillary mucinous neoplasm; ITPN: intraductal tubular papillary neoplasm;JAK: janus kinase; KRAS: Kirsten rat sarcoma virus; PAF1: polymerase-associated factor 1; PanIN: pancreatic intraepithelial neoplasia; PDAC: Pancreatic ductal adenocarcinoma; PI3K: phosphoinositide 3-kinase; SOX9: sex-determining region Y-box 9; STAT: signal transducer and activator of transcription; TAZ: Transcriptional co-activator with PDZ-binding domain; YAP: Yes-associated protein

Fig. 5

Hippo pathway dysregulation from bowel precursor lesions to malignancy. Mechanisms of aberrant YAP/TAZ activation associated with inflammatory bowel disease and adenomas/adenomatous polyps. APC: adenomatous polypolis coli; CREBP: cAMP response element-binding protein; IL-6: interleukin 6/; INF-γ: interferon-gamma; LATS1: large tumor suppressor 1; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; PGE2: prostaglandin E2; PKA: protein kinase A; REG-γ: proteasome activator subunit 3; ROCK1: Rho-associated protein kinase 1; SSP: sessile serrated polyps; YAP: Yes-associated protein