Tyrosine phosphorylation-mediated YAP1-TFAP2A interactions coordinate transcription and trastuzumab resistance in HER2+ breast cancer.

Trastuzumab resistance in HER2+ breast cancer (BC) is the major reason leading to poor prognosis of BC patients. Oncogenic gene overexpression or aberrant activation of tyrosine kinase SRC is identified to be the key modulator of trastuzumab response. However, the detailed regulatory mechanisms underlying SRC activation-associated trastuzumab resistance remain poorly understood. In the present study, we discover that SRC-mediated YAP1 tyrosine phosphorylation facilitates its interaction with transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha, TFAP2A), which in turn promotes YAP1/TEAD-TFAP2A (YTT) complex-associated transcriptional outputs, thereby conferring trastuzumab resistance in HER2+ BC. Inhibition of SRC kinase activity or disruption of YTT complex sensitizes cells to trastuzumab treatment in vitro and in vivo. Additionally, we also identify YTT complex co-occupies the regulatory regions of a series of genes related to trastuzumab resistance and directly regulates their transcriptions, including EGFR, HER2, H19 and CTGF. Moreover, YTT-mediated transcriptional regulation is coordinated by SRC kinase activity. Taken together, our study reveals that SRC-mediated YTT complex formation and transcriptions are responsible for multiple mechanisms associated with trastuzumab resistance. Therefore, targeting HER2 signaling in combination with the inhibition of YTT-associated transcriptional outputs could serve as the treatment strategy to overcome trastuzumab resistance caused by SRC activation.

In vitro characterization of alternative l-threonate and d-erythronate catabolic pathways.

l-threonate is the metabolite of vitamin C, while d-erythronate is the metabolite of N-acetyl-d-glucosamine, the nutritional supplement for joint health. They are widely distributed in the environment and human biofluids. Nevertheless, the catabolisms of l-threonate and d-erythronate are sparsely reported. Here we explored the functional diversity of an acid sugar kinase family (Pfam families PF07005-PF17042), and discovered a novel 2-oxo-tetronate kinase. The conserved genome neighborhood of the 2-oxo-tetronate kinase encodes members of class-II fructose-bisphosphate aldolase family (F_bP_aldolase, PF01116) and a dehydrogenase family (PF03446-PF14833). Instructed by this analysis, we experimentally verified that these enzymes are capable of degrading l-threonate into dihydroxyacetone phosphate (DHAP) in Arthrobacter sp. ZBG10, Clostridium scindens ATCC 35704, and Pseudonocardia dioxanivorans ATCC 55486. Meanwhile, a convergent catabolic pathway for d-erythronate was characterized in P. dioxanivorans ATCC 55486. Moreover, the phylogenetic distribution analysis indicates that the biological range of the identified l-threonate and d-erythronate catabolic pathways appears to extend mostly to members of the Actinomycetota, Cyanobacteriota, Bacillota, Pseudomonadota, and Bacteroidota phyla.

3D-printed bredigite scaffolds with ordered arrangement structures promote bone regeneration by inducing macrophage polarization in onlay grafts.

Bone tissue engineering scaffolds may provide a potential strategy for onlay bone grafts for oral implants. For determining the fate of scaffold biomaterials and osteogenesis effects, the host immune response is crucial. In the present study, bredigite (BRT) bioceramic scaffolds with an ordered arrangement structure (BRT-O) and a random morphology (BRT-R) were fabricated. The physicochemical properties of scaffolds were first characterized by scanning electron microscopy, mechanical test and micro-Fourier transform infrared spectroscopy. In addition, their osteogenic and immunomodulatory properties in an onlay grafting model were investigated. In vitro, the BRT-O scaffolds facilitated the macrophage polarization towards a pro-regenerative M2 phenotype, which subsequently facilitated the migration and osteogenic differentiation of bone marrow-derived mesenchymal stem cells. In vivo, an onlay grafting model was successfully established in the cranium of rabbits. In addition, the BRT-O scaffolds grafted on rabbit cranium promoted bone regeneration and CD68 + CD206 + M2 macrophage polarization. In conclusion, the 3D-printed BRT-O scaffold presents as a promising scaffold biomaterial for onlay grafts by regulating the local immune microenvironment.

Electrical aligned polyurethane nerve guidance conduit modulates macrophage polarization and facilitates immunoregulatory peripheral nerve regeneration.

Biomaterials can modulate the local immune microenvironments to promote peripheral nerve regeneration. Inspired by the spatial orderly distribution and endogenous electric field of nerve fibers, we aimed to investigate the synergistic effects of electrical and topological cues on immune microenvironments of peripheral nerve regeneration. Nerve guidance conduits (NGCs) with aligned electrospun nanofibers were fabricated using a polyurethane copolymer containing a conductive aniline trimer and degradable L-lysine (PUAT). In vitro experiments showed that the aligned PUAT (A-PUAT) membranes promoted the recruitment of macrophages and induced their polarization towards the pro-healing M2 phenotype, which subsequently facilitated the migration and myelination of Schwann cells. Furthermore, NGCs fabricated from A-PUAT increased the proportion of pro-healing macrophages and improved peripheral nerve regeneration in a rat model of sciatic nerve injury. In conclusion, this study demonstrated the potential application of NGCs in peripheral nerve regeneration from an immunomodulatory perspective and revealed A-PUAT as a clinically-actionable strategy for peripheral nerve injury.

Tyrosine kinase SRC-induced YAP1-KLF5 module regulates cancer stemness and metastasis in triple-negative breast cancer.

SRC is the first identified oncogene, and its aberrant activation has been implicated as a driving event in tumor initiation and progression. However, its role in cancer stemness regulation and the underlying regulatory mechanism are still elusive. Here, we identified a YAP1 tyrosine phosphorylation-dependent YAP1-KLF5 oncogenic module, as the key downstream mediator of SRC kinase regulating cancer stemness and metastasis in triple-negative breast cancer (TNBC). SRC was overexpressed in TNBC patient tissues and its expression level was highly correlated with the tumor malignancy. SRC activation induced, while inhibition of SRC kinase reduced the cancer stemness, tumor cell growth and metastasis in vitro and in vivo. Transcriptomic and proteomic analysis revealed that SRC-mediated YAP1 tyrosine phosphorylation induced its interaction with Kruppel-like factor 5 (KLF5) to form a YAP1/TEAD-KLF5 complex in TNBC cells. YAP1-KLF5 association further promoted TEAD-mediated transcriptional program independently of canonical Hippo kinases, which eventually gave rise to the enhanced cancer stemness and metastasis. Disruption of YAP1-KLF5 module in TNBC cells dramatically attenuated the SRC-induced cancer stemness and metastasis in vitro and in vivo. Accordingly, co-upregulations of SRC and YAP1-KLF5 module in TNBC tissues were significantly positively correlated with the tumor malignance. Altogether, our work presents a novel tyrosine phosphorylation-dependent YAP1-KLF5 oncogenic module governing SRC-induced cancer stemness and metastasis in TNBC. Therefore, targeting YAP1/KLF5-mediated transcription may provide a promising strategy for TNBC treatment with SRC aberrantly activation.

Predicting chronological age of 14 or 18 in adolescents: integrating dental assessments with machine learning.

AIM: Age estimation plays a critical role in personal identification, especially when determining compliance with the age of consent for adolescents. The age of consent refers to the minimum age at which an individual is legally considered capable of providing informed consent for sexual activities. The purpose of this study is to determine whether adolescents meet the age of 14 or 18 by using dental development combined with machine learning. METHODS: This study combines dental assessment and machine learning techniques to predict whether adolescents have reached the consent age of 14 or 18. Factors such as the staging of the third molar, the third molar index, and the visibility of the periodontal ligament of the second molar are evaluated. RESULTS: Differences in performance metrics indicate that the posterior probabilities achieved by machine learning exceed 93% for the age of 14 and slightly lower for the age of 18. CONCLUSION: This study provides valuable insights for forensic identification for adolescents in personal identification, emphasizing the potential to improve the accuracy of age determination within this population by combining traditional methods with machine learning. It underscores the importance of protecting and respecting the dignity of all individuals involved.

The oncogenic roles and clinical implications of YAP/TAZ in breast cancer.

Breast cancer (BC) is the most commonly diagnosed form of cancer and a leading cause of cancer-related deaths among women worldwide. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are homologous transcriptional coactivators and downstream effectors of Hippo signalling. YAP/TAZ activation has been revealed to play essential roles in multiple events of BC development, including tumour initiation, progression, metastasis, drug resistance and stemness regulations. In this review, we will first give an overview of YAP/TAZ-mediated oncogenesis in BC, and then systematically summarise the oncogenic roles of YAP/TAZ in various BC subtypes, BC stem cells (BCSCs) and tumour microenvironments (TMEs). Based on these findings, we will further discuss the clinical implications of YAP/TAZ-based targeted therapies in BC and the potential future direction.

Three-dimensional assessment of tongue cancer prognosis by preoperative MRI.

PURPOSE: To obtain the relative volume by measuring the tongue volume and the lesion volume, and further explore its relationship with the prognosis of patients, hoping to supplement the TNM staging with a new index. METHODS: ITK-SANP software was used to outline the patients' MRI. After MRI reconstruction and measurement, slicer software was used to estimate tumor volume. RESULTS: A total of 64 patients with tongue cancer who met the inclusion criteria were included in the study. The estimated tumor volume after MRI reconstruction revealed a significant and robust correlation with tumor stage (p < 0.05, Rs = 0.6207) and a substantial and medium correlation with early lymph node metastasis (p < 0.05, Rs = 0.4873). CONCLUSIONS: We classified tongue cancer into three grades based on tumor volume (Stage I, tumors smaller than 1500 mm³; Stage II, tumors 1500-9000 mm³; and Stage III, tumors larger than 9000 mm³), and such grading could be used as a reference for tumor staging, lymph node metastasis, and patient prognosis to a certain extent.

SRC kinase-mediated signaling pathways and targeted therapies in breast cancer.

Breast cancer (BC) has been ranked the most common malignant tumor throughout the world and is also a leading cause of cancer-related deaths among women. SRC family kinases (SFKs) belong to the non-receptor tyrosine kinase (nRTK) family, which has eleven members sharing similar structure and function. Among them, SRC is the first identified proto-oncogene in mammalian cells. Oncogenic overexpression or activation of SRC has been revealed to play essential roles in multiple events of BC progression, including tumor initiation, growth, metastasis, drug resistance and stemness regulations. In this review, we will first give an overview of SRC kinase and SRC-relevant functions in various subtypes of BC and then systematically summarize SRC-mediated signaling transductions, with particular emphasis on SRC-mediated substrate phosphorylation in BC. Furthermore, we will discuss the progress of SRC-based targeted therapies in BC and the potential future direction.

Field Effect Conductivities of P-I-N Heterostructure Films in Fuel Cells.

Ionic conductivity enables the technologies of fuel cells, electrolysis cells, and batteries. However, the ambiguous origins of the extraordinary ionic conductivity impede its implementation in heterostructure films for the devices. Here, we disclosed that the extraordinary ionic and electronic conductivities come from field effect. We found in Ce0.8Gd0.2O2-δ (CGO)/Zr0.85Y0.15O2-δ (YSZ) heterostructures that the ionic conductivity of CGO layer (n-i conductor) and the electronic conductivity of YSZ layer (p-i conductor) exponentially increased with potential. The potential occurred from electron transfer and stoichiometric polarization in p-i-n junction. Field effect ionic conductivity contributed the major increment in the maximum power density. The results demonstrated field effect ionic and electronic conductivities, their dependences on heterostructures, and impacts on fuel cells.

Three-Dimensional Graphene-Based Macrostructures for Electrocatalysis.

Electrochemical energy storage and conversion is an effective strategy to relieve the increasing energy and environment crisis. The sluggish reaction kinetics in the related devices is one of the major obstacles for them to realize practical applications. More efforts should be devoted to searching for high-efficiency electrocatalysts and enhancing the electrocatalytic performance. 3D graphene macrostructures (3D GMs) are one kind of porous crystalline materials with 3D structures at both micro- and macro-scale. The unique structure can achieve large accessible surface area, expose many active sites, promote fast mass/electron transport, and provide wide room for further functional modification. All these features make them promising candidates for electrocatalysis. In this review, the authors focus on the latest progress of 3D GMs for electrocatalysis. First, the preparation methods of 3D GMs are introduced followed by the strategies for functional modifications. Then, their electrocatalytic performances are discussed in detail including monofunctional and bifunctional electrocatalysis. The electrocatalytic processes involve oxygen reduction reaction, oxygen evolution reaction, hydrogen evolution reaction, and carbon dioxide reduction reaction. Finally, the challenges and perspectives are presented to offer a guideline for the exploration of excellent 3D GM-based electrocatalysts.

[Visual analysis of coronavirus disease 2019 (COVID-19) studies based on bibliometrics].

To analyze the development of coronavirus disease 2019(COVID-19), this study systematically retrieved relevant Chinese and English literatures from both CNKI and Web of Science database platforms by bibliometric research method and CiteSpace 5.5.R2 software to obtain information and visualize relevant literatures. A total of 695 Chinese and 446 English literatures were included in this paper. Statistics showed that China had published most of the literatures and established close cooperation with the United States and the United Kingdom. Through the analysis, Tongji Medical College of Huazhong University of Science and Technology and its affiliated hospitals published the largest number of the publications. Moreover, the highly productive journals including Journal of Traditional Chinese Medicine and The Lancet covered eight major fields, such as medicine, medical virology, radiation medicine, infectious disease, and traditional Chinese medicine. Besides, a total of 35 special COVID-19 funds were recently established to subsidize these studies. The key words and themes analysis indicated that protein structure of COVID-19, receptor targets and mechanisms of action, integration of traditional Chinese and Western medicine, screening and development of antiviral drugs from traditional Chinese medicine and Western medicine, vaccine research as well as epidemiological characteristics and prediction are current study hotspots. This study provides a reference for researchers to rapidly master main study directions of COVID-19 and screen out relevant literatures.

Fibroblast growth factor 19 improves cardiac function and mitochondrial energy homoeostasis in the diabetic heart.

In diabetic cardiomyopathy, mitochondrial fatty acid oxidation dominates over mitochondrial glucose oxidation, leading to metabolic disturbances. Fibroblast growth factor 19 (FGF19) acts as a metabolic regulator and may have a cardioprotective role on diabetic cardiomyopathy. In this study, we investigated the effects of FGF19 on energy metabolism. FGF19 treatment of diabetic hearts exhibited higher glucose uptake and lower lipid profiles, suggesting changes in energy metabolism. The protective effects of FGF19 prevented ventricular dysfunction in diabetic hearts and improved mitochondrial function by the upregulation of PGC-1α expression. On the other side, knockdown of PGC-1α by siRNA attenuated the effects of FGF19 on the enhancement of mitochondrial function and energy efficiency. Taken together, these results show that FGF19 exhibited improved mitochondrial efficiency, which might be associated with higher cardiac contractility in diabetic hearts. It is also of note that modulation of PGC-1α, which is responsible for the activation by FGF19, may be a therapeutic target for diabetic cardiomyopathy.

The effect of consolidation chemotherapy after concurrent chemoradiotherapy on the survival of patients with locally advanced non-small cell lung cancer: a meta-analysis.

Whether consolidation chemotherapy (CCT) after chemoradiotherapy (CRT) helps in the treatment of locally advanced non-small cell lung cancer (LA-NSCLC) is controversial. The aim of this meta-analysis was to evaluate the impact of CCT on overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and toxicities in patients with inoperable LA-NSCLC. PubMed, Embase, The Cochrane Library, WanFang, VIP, and CNKI were searched to identify any relevant publications. After screening the literature and completing quality assessment and data extraction, the meta-analysis was performed using RevMan5.3 software. Ultimately, 5 eligible studies with a total of 1036 patients were selected for the present meta-analysis. The results of the analysis indicated that treatment of LA-NSCLC patients with CRT followed by CCT improved OS (pooled HR 0.85; 95% CI 0.73-0.99; P = 0.03), but did not improve PFS (pooled HR 0.78; 95% CI 0.60-1.02; P = 0.07) and ORR (P = 0.26). Although it could increase the risk of grade ≥3 infection (P = 0.04), it may not increase the risk of grade ≥3 radiation pneumonitis (P = 0.09) during the CCT period. CCT after concurrent CRT may provide additional benefits in the treatment of LA-NSCLC. Although this therapeutic strategy did not prolong PFS, further assessment is warranted.

Enhancing lipid peroxidation via radical chain transfer reaction for MRI guided and effective cancer therapy in mice.

Lipid peroxidation (LPO), the process of membrane lipid oxidation, is a potential new form of cell death for cancer treatment. However, the radical chain reaction involved in LPO is comprised of the initiation, propagation (the slowest step), and termination stages, limiting its effectiveness in vivo. To address this limitation, we introduce the radical chain transfer reaction into the LPO process to target the propagation step and overcome the sluggish rate of lipid peroxidation, thereby promoting endogenous lipid peroxidation and enhancing therapeutic outcomes. Firstly, radical chain transfer agent (CTA-1)/Fe nanoparticles (CTA-Fe NPs-1) was synthesized. Notably, CTA-1 convert low activity peroxyl radicals (ROO·) into high activity alkoxyl radicals (RO·), creating the cycle of free radical oxidation and increasing the propagation of lipid peroxidation. Additionally, CTA-1/Fe ions enhance reactive oxygen species (ROS) generation, consume glutathione (GSH), and thereby inactivate GPX-4, promoting the initiation stage and reducing termination of free radical reaction. CTA-Fe NPs-1 induce a higher level of peroxidation of polyunsaturated fatty acids in lipid membranes, leading to highly effective treatment in cancer cells. In addition, CTA-Fe NPs-1 could be enriched in tumors inducing potent tumor inhibition and exhibit activatable T1-MRI contrast of magnetic resonance imaging (MRI). In summary, CTA-Fe NPs-1 can enhance intracellular lipid peroxidation by accelerating initiation, propagation, and inhibiting termination step, promoting the cycle of free radical reaction, resulting in effective anticancer outcomes in tumor-bearing mice.

Pancoronary plaque characteristics in STEMI patients with rapid plaque progression: An optical coherence tomography study.

BACKGROUND: Non-culprit plaque progression is associated with recurrent cardiac ischemic events and worse clinical outcomes. Given that atherosclerosis is a systemic disease, the pancoronary characteristics of patients with rapid plaque progression are unknown. This study aims to identify pancoronary plaque features in patients with ST-segment elevation myocardial infarction (STEMI) with and without rapid plaque progression, focused on the patient level. METHODS AND RESULTS: From January 2017 to July 2019, 291 patients underwent 3-vessel optical coherence tomography imaging at the time of the primary procedure and a follow-up angiography interval of 12 months. The final analysis included 237 patients. Overall, 308 non-culprit lesions were found in 78 STEMI patients with rapid plaque progression, and 465 non-culprit plaques were found in 159 STEMI patients without rapid plaque progression. These patients had a higher pancoronary vulnerability (CLIMA-defined high-risk plaque: 47.4% vs. 33.3%; non-culprit plaque rupture: 25.6% vs. 14.5%) and a significantly higher prevalence of other vulnerable plaque characteristics (i.e., lipid-rich plaque, cholesterol crystal, microchannels, calcification, spotty calcification, and thrombus) at baseline versus those without rapid plaque progression. Lesions with rapid progression were highly distributed at the LAD, tending to be near the bifurcation. In multivariate analysis, age ≥ 65 years was an independent predictor of subsequent rapid lesion progression at the patient level, whereas microchannel, spotty calcification, and cholesterol crystal were independent predictors for STEMI patients ≥65 years old. CONCLUSIONS: STEMI patients with subsequent rapid plaque progression had higher pancoronary vulnerability and commonly presented vulnerable plaque morphology. Aging was the only predictor of subsequent rapid plaque progression.

Capecitabine or Capecitabine Plus Oxaliplatin Versus Fluorouracil Plus Cisplatin in Definitive Concurrent Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma (CRTCOESC): A Multicenter, Randomized, Open-Label, Phase 3 Trial.

PURPOSE: This phase 3 trial aimed to compare the efficacy and safety of capecitabine or capecitabine plus oxaliplatin (XELOX) with those of fluorouracil plus cisplatin (PF) in definitive concurrent chemoradiotherapy (DCRT) for inoperable locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Patients were randomly assigned to receive two cycles of capecitabine, XELOX, or PF along with concurrent intensity-modulated radiation therapy. Patients in each arm were again randomly assigned to receive two cycles of consolidation chemotherapy or not. The primary end points were 2-year overall survival (OS) rate and incidence of grade ≥3 adverse events (AEs). RESULTS: A total of 246 patients were randomly assigned into the capecitabine (n = 80), XELOX (n = 85), and PF (n = 81) arms. In capecitabine, XELOX, and PF arms, the 2-year OS rate was 75%, 66.7%, and 70.9% (capecitabine v PF: hazard ratio [HR], 0.91 [95% CI, 0.61 to 1.35]; nominal P = .637; XELOX v PF: 0.86 [95% CI, 0.58 to 1.27]; P = .444); the median OS was 40.9 (95% CI, 34.4 to 49.9), 41.9 (95% CI, 28.6 to 52.1), and 35.4 (95% CI, 30.4 to 45.4) months. The incidence of grade ≥3 AEs during the entire treatment was 28.8%, 36.5%, and 45.7%, respectively. Comparing the consolidation chemotherapy with the nonconsolidation chemotherapy groups, the median OS was 41.9 (95% CI, 34.6 to 52.8) versus 36.9 (95% CI, 28.5 to 44) months (HR, 0.71 [95% CI, 0.52 to 0.99]; nominal P = .0403). CONCLUSION: Capecitabine or XELOX did not significantly improve the 2-year OS rate over PF in DCRT for inoperable locally advanced ESCC. Capecitabine showed a lower incidence of grade ≥3 AEs than PF did.

Decarburization of Wire-Arc Additively Manufactured ER70S-6 Steel.

Decarburization is an unwanted carbon-loss phenomenon on the surfaces of a material when they are exposed to oxidizing environments at elevated temperatures. Decarburization of steels after heat treatment has been widely studied and reported. However, up to now, there has not been any systematic study on the decarburization of additively manufactured parts. Wire-arc additive manufacturing (WAAM) is an efficient additive manufacturing process for producing large engineering parts. As the parts produced by WAAM are usually large in size, the use of a vacuum environment to prevent decarburization is not always feasible. Therefore, there is a need to study the decarburization of WAAM-produced parts, especially after the heat treatment processes. This study investigated the decarburization of a WAAM-produced ER70S-6 steel using both the as-printed material and samples heat-treated at different temperatures (800 °C, 850 °C, 900 °C, and 950 °C) for different durations (30 min, 60 min, and 90 min). Furthermore, numerical simulation was carried out using Thermo-Calc computational software to predict the carbon concentration profiles of the steel during the heat treatment processes. Decarburization was found to occur not only in the heat-treated samples but also on the surfaces of the as-printed parts (despite the use of Ar for shielding). The decarburization depth was found to increase with an increase in heat treatment temperature or duration. The part heat-treated at the lowest temperature of 800 °C for merely 30 min was observed to have a large decarburization depth of about 200 µm. For the same heating duration of 30 min, an increase in temperature of 150 °C to 950 °C increased the decarburization depth drastically by 150% to 500 µm. This study serves well to demonstrate the need for further study to control or minimize decarburization for the purpose of ensuring the quality and reliability of additively manufactured engineering components.

Prediction and validation of monoclonal antibodies separation in aqueous two-phase system using molecular dynamic simulation.

In order to predict how mAbs partition in 20% ethylene oxide/80% propylene oxide (v/v) random copolymer (EO20PO80)/water aqueous two-phase system (ATPS), a molecular dynamic simulation model was developed using Gromacs and then validated by experiments. The ATPS was applied with seven kinds of salt, including buffer salt and strong dissociation salt that were commonly employed in the purification of protein. Na2SO4 was shown to have the best effects on lowering EO20PO80 content in the aqueous phase and enhancing recovery. The content of EO20PO80 in the sample solution was decreased to 0.62%±0.25% and the recovery of rituximab increased to 97.88%±0.95% by adding 300 mM Na2SO4 into back extraction ATPS. The viability determined by ELISA was 95.57% at the same time. A strategy for constructing a prediction model for the distribution of mAbs in ATPS was proposed in consideration of this finding. Partition of trastuzumab in ATPS was predicted by the model created using this method and the prediction result was further validated by experiments. The recovery of trastuzumab reached 95.63%±2.86% under the ideal extraction conditions suggested by the prediction model.

New insights into the ambivalent role of YAP/TAZ in human cancers.

Hippo signaling was first identified in Drosophila as a key controller of organ size by regulating cell proliferation and anti-apoptosis. Subsequent studies have shown that this pathway is highly conserved in mammals, and its dysregulation is implicated in multiple events of cancer development and progression. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) (hereafter YAP/TAZ) are the downstream effectors of the Hippo pathway. YAP/TAZ overexpression or activation is sufficient to induce tumor initiation and progression, as well as recurrence and therapeutic resistance. However, there is growing evidence that YAP/TAZ also exert a tumor-suppressive function in a context-dependent manner. Therefore, caution should be taken when targeting Hippo signaling in clinical trials in the future. In this review article, we will first give an overview of YAP/TAZ and their oncogenic roles in various cancers and then systematically summarize the tumor-suppressive functions of YAP/TAZ in different contexts. Based on these findings, we will further discuss the clinical implications of YAP/TAZ-based tumor targeted therapy and potential future directions.