Yuhang Zhou

The TEAD Family and Its Oncogenic Role in Promoting Tumorigenesis.

The TEAD family of transcription factors is necessary for developmental processes. The family members contain a TEA domain for the binding with DNA elements and a transactivation domain for the interaction with transcription coactivators. TEAD proteins are required for the participation of coactivators to transmit the signal of pathways for the downstream signaling processes. TEADs also play an important role in tumor initiation and facilitate cancer progression via activating a series of progression-inducing genes, such as CTGF, Cyr61, Myc and Gli2. Recent studies have highlighted that TEADs, together with their coactivators, promote or even act as the crucial parts in the development of various malignancies, such as liver, ovarian, breast and prostate cancers. Furthermore, TEADs are proposed to be useful prognostic biomarkers due to the ideal correlation between high expression and clinicopathological parameters in gastric, breast, ovarian and prostate cancers. In this review, we summarize the functional role of TEAD proteins in tumorigenesis and discuss the key role of TEAD transcription factors in the linking of signal cascade transductions. Improved knowledge of the TEAD proteins will be helpful for deep understanding of the molecular mechanisms of tumorigenesis and identifying ideal predictive or prognostic biomarkers, even providing clinical translation for anticancer therapy in human cancers.

miR-508-3p concordantly silences NFKB1 and RELA to inactivate canonical NF-κB signaling in gastric carcinogenesis

BackgroundNF-κB signaling pathway plays an important role in gastric carcinogenesis. The basic expression and functional role of NFKB1 and RELA (components of canonical NF-κB pathway) in gastric cancer (GC) have not been well elucidated. In this study, the role of NFKB1 and RELA in gastric tumorigenesis will be investigated and their regulation by microRNAs (miRNAs) will be deeply explored.MethodsThe mRNA and protein expression of NFKB1 and RELA were investigated by qRT-PCR and Western blot in GC cell lines and primary tumors. The functional roles of NFKB1 and RELA in GC were demonstrated by MTT proliferation assay, monolayer colony formation, cell invasion and migration, cell cycle analysis and in vivo study through siRNA mediated knockdown. Identification of NFKB1 as a direct target of tumor suppressor miRNA miR-508-3p was achieved by expression regulation assays together with dual luciferase activity experiments.ResultsNFKB1 and RELA were up-regulated in GC cell lines and primary tumors compared with normal gastric epithelium cells and their upregulation correlation with poor survival in GC. siRNA mediated knockdown of NFKB1 or RELA exhibited anti-oncogenic effect both in vitro and in vivo. NFKB1 was further revealed to be a direct target of miR-508-3p in gastric tumorigenesis and their expression showed negative correlation in primary GC samples. miR-508-3p was down-regulated in GC cells compared with normal gastric epithelium samples and its ectopic expression in GC cell lines also exerts tumor suppressor function. NFKB1 re-expression was found to partly abolish the tumor-suppressive effect of miR-508-3p in GC.ConclusionAll these findings supports that canonical NF-κB signaling pathway is activated in GC at least by the inactivation of miR-508-3p and this might have therapeutic potential in GC treatment.

The Interplay of LncRNA-H19 and Its Binding Partners in Physiological Process and Gastric Carcinogenesis

Long non-coding RNA (lncRNA), a novel and effective modulator in carcinogenesis, has become a study hotspot in recent years. The imprinted oncofetal lncRNA H19 is one of the first identified imprinted lncRNAs with a high expression level in embryogenesis but is barely detectable in most tissues after birth. Aberrant alterations of H19 expression have been demonstrated in various tumors, including gastric cancer (GC), implicating a crucial role of H19 in cancer progression. As one of the top malignancies in the world, GC has already become a serious concern to public health with poor prognosis. The regulatory roles of H19 in gastric carcinogenesis have been explored by various research groups, which leads to the development of GC therapy. This review comprehensively summarizes the current knowledge of H19 in tumorigenesis, especially in GC pathogenesis, with emphasis on the underneath molecular mechanisms depicted from its functional partners. Furthermore, the accumulated knowledge of H19 will provide better understanding on targeted therapy of GC.

The oncogenic role of Epstein–Barr virus‐encoded microRNAs in Epstein–Barr virus‐associated gastric carcinoma

Epstein–Barr virus (EBV) infection is detected in various epithelial malignancies, such as nasopharyngeal carcinoma (NPC) and gastric cancer (GC). EBV comprises some unique molecular features and encodes viral genes and microRNAs (miRNAs) by its own DNA sequence. EBV genes are required to maintain latency and contribute to oncogenic property. miRNAs encoded by EBV have been shown to contribute to initiation and progression of EBV‐related malignancies. By a number of genomic profiling studies, some EBV miRNAs were confirmed to be highly expressed in EBV‐associated gastric cancer (EBVaGC) samples and cell lines. The majority host targets of the EBV miRNAs are important for promoting cell growth and inhibiting apoptosis, facilitating cell survival and immune evasion. However, the integrated molecular mechanisms related to EBV miRNAs remain to be investigated. In this review, we summarized the crucial role of EBV miRNAs in epithelial malignancies, especially in EBVaGC. Collectively, EBV miRNAs play a significant role in the viral and host gene regulation network. Understanding the comprehensive potential targets and relevant functions of EBV miRNAs in gastric carcinogenesis might provide better clinical translation.

NOTCH receptors in gastric and other gastrointestinal cancers: oncogenes or tumor suppressors?

Gastric cancer (GC) ranks the most common cancer types and is one of the leading causes of cancer-related death. Due to delayed diagnosis and high metastatic frequency, 5-year survival rate of GC is rather low. It is a complex disease resulting from the interaction between environmental factors and host genetic alterations that deregulate multiple signaling pathways. The Notch signaling pathway, a highly conserved system in the regulation of the fate in several cell types, plays a pivotal role in cell differentiation, survival and proliferation. Notch is also one of the most commonly activated signaling pathways in tumors and its aberrant activation plays a key role in cancer advancement. Whether Notch cascade exerts oncogenic or tumor suppressive function in different cancer types depends on the cellular context. Mammals have four NOTCH receptors that modulate Notch pathway activity. In this review, we provide a comprehensive summary on the functional role of NOTCH receptors in gastric and other gastrointestinal cancers. Increasing knowledge of NOTCH receptors in gastrointestinal cancers will help us recognize the underlying mechanisms of Notch signaling and develop novel therapeutic strategies for GC.

IGF2BP3 functions as a potential oncogene and is a crucial target of miR-34a in gastric carcinogenesis

BackgroundGastric cancer (GC) is one of the frequent causes of cancer-related death in eastern Asian population. IGF2BP2 lists in the top rank up-regulated genes in GC, but its functional role is unclear.MethodThe expression of IGF2BP3 in GC cell lines and primary samples was examined by qRT-PCR and Western blot. The biological role of IGF2BP3 was revealed by a series of functional in vitro studies. Its regulation by microRNAs (miRNAs) was predicted by TargetScan and confirmed by luciferase assays and rescue experiments.ResultsIGF2BP3 ranked the No.1 of the up-regulated genes by expression microarray analysis in GC cell lines. The expression level of IGF2BP3 was observed in GC tissues comparing with non-tumorous gastric epitheliums. The up-regulated IGF2BP3 expression was associated with poor disease specific survival. IGF2BP3 knockdown significantly inhibited cell proliferation and invasion. Apart from copy number gain, IGF2BP3 has been confirmed to be negatively regulated by tumor-suppressive miRNA, namely miR-34a. The expression of miR-34a showed negative correlation with IGF2BP3 mRNA expression in primary GC samples and more importantly, re-overexpression of IGF2BP3 rescued the inhibitory effect of miR-34a.ConclusionWe compressively revealed the oncogenic role of IGF2BP3 in gastric tumorigenesis and confirmed its activation is partly due to the silence of miR-34a. Our findings identified useful prognostic biomarker and provided clinical translational potential.

TEAD1/4 exerts oncogenic role and is negatively regulated by miR-4269 in gastric tumorigenesis

TEA domain (TEAD) transcription factors are key components of the Hippo–YAP1 signaling pathway, but their functional role and regulatory mechanisms remain unclear. This study aims to comprehensively explore the expression pattern and functional role of TEAD family in gastric carcinogenesis and investigate its regulation by microRNAs (miRNAs). The mRNA and protein expression of TEAD family were examined by quantitative reverse transcription–PCR (qRT–PCR) and western blot. Their functional roles were determined by in vitro and in vivo studies. The clinicopathological association of TEAD4 in gastric cancer (GC) was studied using immunohistochemistry on tissue microarray. The prediction of miRNAs, which potentially target TEAD1/4, was performed by TargetScan and miRDB. The regulation of TEAD1/4 by miRNAs was confirmed by qRT–PCR, western blot and luciferase assays. TEAD1/4 were overexpressed in GC cell lines and primary GC tissues. Knockdown of TEAD1/4 induced a significant anticancer effect in vitro and in vivo. TEAD1 was confirmed to be a direct target of miR-377-3p and miR-4269, while TEAD4 was negatively regulated by miR-1343-3p and miR-4269. Among them, miR-4269 was the most effective inhibitor of TEAD1/4. Ectopic expression of these miRNAs substantiated their tumor-suppressive effects. In primary GC tumors, downregulation of miR-4269 was associated with poor disease-specific survival and showed a negative correlation with TEAD4. TEAD1 and TEAD4 are oncogenic factors, whose aberrant activation are, in part, mediated by the silence of miR-377-3p, miR-1343-3p and miR-4269. For the first time, the nuclear accumulated TEAD4 and downregulated miR-4269 are proposed to serve as novel prognostic biomarkers in GC.

SRGAP1, a crucial target of miR-340 and miR-124, functions as a potential oncogene in gastric tumorigenesis

Slit-Robo GTPase-activating protein 1 (SRGAP1) functions as a GAP for Rho-family GTPases and downstream of Slit-Robo signaling. We aim to investigate the biological function of SRGAP1 and reveal its regulation by deregulated microRNAs (miRNAs) in gastric cancer (GC). mRNA and protein expression of SRGAP1 were examined by quantitative reverse transcription PCR (qRT-PCR) and western blot. The biological role of SRGAP1 was demonstrated through siRNA-mediated knockdown experiments. The regulation of SRGAP1 by miR-340 and miR-124 was confirmed by western blot, dual luciferase activity assays and rescue experiments. SRGAP1 is overexpressed in 9 out of 12 (75.0%) GC cell lines. In primary GC samples from TCGA cohort, SRGAP1 shows gene amplification in 5/258 (1.9%) of cases and its mRNA expression demonstrates a positive correlation with copy number gain. Knockdown of SRGAP1 in GC cells suppressed cell proliferation, reduced colony formation, and significantly inhibited cell invasion and migration. Luciferase reporter assays revealed that SRGAP1 knockdown significantly inhibited Wnt/β-catenin pathway. In addition, SRGAP1 was found to be a direct target of two tumor-suppressive miRNAs, miR-340 and miR-124. Concordantly, these two miRNAs were downregulated in primary gastric tumors and these decreasing levels w5ere associated with poor outcomes. Expression of miR-340 and SRGAP1 displayed a reverse relationship in primary samples and re-expressed SRGAP1, rescued the anti-cancer effects of miR-340. Taken together, these data strongly suggest that, apart from gene amplification and mutation, the activation of SRGAP1 in GC is partly due to the downregulation of tumor-suppressive miRNAs, miR-340 and miR-124. Thus SRGAP1 is overexpressed in gastric carcinogenesis and plays an oncogenic role through activating Wnt/β-catenin pathway.

PIEZO1 functions as a potential oncogene by promoting cell proliferation and migration in gastric carcinogenesis

Gastric cancer (GC) is one of the most common malignancies in Asian areas. PIEZO1 has been implied to regulate epithelial homeostasis to play an important role in physiological processes. It is also related to tumor initiation and progression. However, the role of PIEZO1 has not yet been explored in GC. The expression of PIEZO1 in GC cell lines and primary samples was determined by qRT‐PCR and Western blot. The clinical correlation of PIEZO1 in GC was evaluated by immunohistochemistry on tissue microarray. The oncogenic role of PIEZO1 was demonstrated in gastric tumorigenesis through a series of functional assays, including cell proliferation, cell invasion, and flow cytometry analysis. Drug sensitivity was also assessed by PIEZO1 knockdown experiment. PIEZO1 exhibited an upregulation in most of the GC cell lines and primary samples compared with non‐tumorous gastric epithelial tissues. Increase of PIEZO1 was associated with poor disease specific survival. PIEZO1 knockdown led to inhibitory effect by suppressing cell proliferation and invasion and inhibiting xenograft formation. Decreased PIEZO1 enhanced the sensitivity of Cisplatin or 5‐FU treatment. Morphological alteration was also observed in siPIEZO1 treated cells. GTP‐Rac1 showed accumulated activated form, while total‐RhoA was decreased accompanied with PIEZO1 knockdown. In the present study, PIEZO1 is required for cell proliferation, migration and invasion to promote GC progression. PIEZO1 also maintains cellular morphology related to GC cell motility by regulating the activity of Rho GTPase family members. Our data not only suggested a novel prognostic marker, but also provided a useful clinical therapeutic target for GC.

Emerging roles of Hippo signaling in inflammation and YAP-driven tumor immunity.

Initially identified as a cell and organ size controller, Hippo pathway turns into a hotspot for researchers. Within recent years, more and more mechanisms about Hippo pathway were uncovered. Even though Hippo signaling has been revealed to exert controversial roles according to different cell context and microenvironment, which is because of its diversified interplays with a great variety of signaling transduction cascades; mechanisms other than size-limitation, however, remain to be elucidated. Recently, a growing number of studies tend to put Hippo on inflammatory and immunological focus: its antimicrobial role in flies, its pro- or anti-inflammation in mammals, as well as its relevance to cancerous immunity. From inflammation to tumor immunogenicity, Hippo has been gradually justified to play a crucial role. This review summarized the latest findings regarding the involvement of Hippo pathway in immunity, and a more comprehensive understanding of Hippo pathway will shed light on clinical translational potential even precision medicine.