Activating Hippo Pathway via Rassf1 by Ursolic Acid Suppresses the Tumorigenesis of Gastric Cancer

Kim, Seong-Hun; Jin, Hua; Meng, Ruo Yu; Kim, Da-Yeah; Liu, Yu Chuan; Chai, Ok Hee; Park, Byung Hyun; Kim, Soo Mi

doi:10.3390/ijms20194709

Cited by 37 publications

(27 citation statements)

References 53 publications

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“…The Hippo signaling pathway is a tumor inhibition pathway that was discovered in recent years, of which LATS1 and LATS2 kinase are two important components and have many important biological functions. LATS1 and LATS2 are involved in the occurrence and development of GC [15].…”

Section: Discussionmentioning

confidence: 99%

Association analysis between SNPs in LATS1 and LATS2 and non-cardia gastric cancer

Tian

Gao

et al. 2020

BMC Gastroenterol

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Background: Many studies have found that large tumor suppressor kinase 1 (LATS1) and LATS2 play important roles in many diseases, but studies have been rare on the relationship between these genes and non-cardia gastric cancer (GC). We performed a case-control association study to investigate the associations between single nucleotide polymorphisms (SNPs) in LATS1 and LATS2 genes and Helicobacter pylori (H. pylori) infection as well as the risk of non-cardia GC. Methods: First, H. pylori infection was determined by the serological test using enzyme-linked immunoassay. Then genotyping of SNPs was performed for 808 samples by the Taqman method. Finally, unconditional logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for age and gender, for the association of each SNP with the infection of H. pylori, the risk of non-cardia gastric cancer, as well as the expression of LATS1 and LATS2 proteins in non-cardia GC tissues, using the codominant, dominant, recessive, overdominant, and log-additive inheritance models, respectively. Results: The statistical results showed that LATS2 rs9552315 was associated with H. pylori infection, and the CC + CT genotype could reduce the risk of H. pylori infection (odds ratio [OR]: 0.549, 95% confidence interval [CI]: 0.339-0.881, P < 0.05) compared with the TT genotype in a dominant model. LATS1 rs9393175 was associated with the risk of non-cardia GC, and the AG genotype reduced the risk of non-cardia GC (OR: 0.702, 95% CI: 0.516-0.952, P < 0.05) compared with the GG + AA genotype in an overdominant model. LATS2 rs9509492 was associated with the risk of GC in an log-additive model. No associations were found between five SNPs and expression of LATS1 and LATS2 proteins in non-cardia GC tissue. Conclusions: LATS2 rs9552315 CT genotype may be a protective factor against infection of H. pylori. LATS1 rs9393175 AG genotype and LATS2 rs9509492 GG genotype may be protective factors for non-cardia GC.

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Section: Discussionmentioning

confidence: 99%

Association analysis between SNPs in LATS1 and LATS2 and non-cardia gastric cancer

Tian

Gao

et al. 2020

BMC Gastroenterol

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“…Although it is a controversial notion that YAP overexpression alone is related to the development of GC, several studies have identified YAP1 as an oncoprotein in the stomach. In normal and proliferating normal gastric epithelium, low or moderate levels of YAP1 expression are detected, whereas significantly elevated YAP1 levels are consistently observed in both primary and metastatic GC [23,24]. YAP1 expression is strongly positively correlated with lymphatic metastasis and shortened overall survival time, indicating that YAP may be used as an independent prognostic marker for GC [25][26][27].…”

Section: Discussionmentioning

confidence: 99%

RP11-323N12.5 promotes the malignancy and immunosuppression of human gastric cancer by increasing YAP1 transcription

et al. 2020

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Background YAP1 is a core protein of the Hippo signaling pathway and is associated with malignancy and immunosuppression. In the present study, we discovered a novel lncRNA, RP11-323N12.5, with tumor promotion and immunosuppression activities through enhancing transcription of YAP1. Methods RP11-323N12.5 was identified using GEPIA. Its expression levels and their relationship with clinical features were investigated using clinical samples. The regulation of YAP1 transcription by RP11-323N12.5 was investigated in both GC and T cells, the tumor and immunosuppression promotion roles of RP11-323N12.5 were explored in vitro and in vivo. Results RP11-323N12.5 was the most up-regulated lncRNA in human GC, based on data from the TCGA database. Its transcription was significantly positively correlated with YAP1 transcription, YAP1 downstream gene expression which contribute to tumor growth and immunosuppression. RP11-323N12.5 promoted YAP1 transcription by binding to c-MYC in the YAP1 promoter region. Meanwhile, transcription of RP11-323N12.5 was also regulated by YAP1/TAZ/TEADs activation in GC cells. RP11-323N12.5 had tumor-and immnosuppression-promoting effects by enhancing YAP1 downstream genes in GC cells. Excessive RP11-323N12.5 was also observed in tumor-infiltrating leukocytes (TILs), which may be exosomederived and also be related to enhanced Treg differentiation as a result YAP1 up-regulation. Moreover, RP11-323N12.5 promoted tumor growth and immunosuppression via YAP1 up-regulation in vivo. Conclusions RP11-323N12.5 was the most up-regulated lncRNA in human GC and it promoted YAP1 transcription by binding to c-MYC within the YAP1 promoter in both GC and T cells. RP11-323N12.5 is an ideal therapeutic target in human GC due to its tumor-promoting and immunosuppression characteristics.

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“…For example, deficiency or inactivation of NF2, which functions to initiate and orchestrate the Hippo pathway ( 58 ), has been reported to be a frequent tumorigenic event in several cancer types ( 64 – 66 ). Furthermore, the upstream regulator of the Hippo pathway, ras association domain family (RASSF), suppresses cancer tumorigenesis ( 67 , 68 ) by regulating MST1/2 activity ( 59 , 60 ). However, how these regulators of the Hippo signaling are simultaneously disrupted in cancers, leading to constitutively inactivation of Hippo signaling, remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Long Non-Coding RNA MAPK8IP1P2 Inhibits Lymphatic Metastasis of Thyroid Cancer by Activating Hippo Signaling via Sponging miR-146b-3p

Liu

Bian

et al. 2021

Front. Oncol.

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The principal issue derived from thyroid cancer is its high propensity to metastasize to the lymph node. Aberrant exprssion of long non-coding RNAs have been extensively reported to be significantly correlated with lymphatic metastasis of thyroid cancer. However, the clinical significance and functional role of lncRNA-MAPK8IP1P2 in lymphatic metastasis of thyroid cancer remain unclear. Here, we reported that MAPK8IP1P2 was downregulated in thyroid cancer tissues with lymphatic metastasis. Upregulating MAPK8IP1P2 inhibited, while silencing MAPK8IP1P2 enhanced anoikis resistance in vitro and lymphatic metastasis of thyroid cancer cells in vivo. Mechanistically, MAPK8IP1P2 activated Hippo signaling by sponging miR-146b-3p to disrupt the inhibitory effect of miR-146b-3p on NF2, RASSF1, and RASSF5 expression, which further inhibited anoikis resistance and lymphatic metastasis in thyroid cancer. Importantly, miR-146b-3p mimics reversed the inhibitory effect of MAPK8IP1P2 overexpression on anoikis resistance of thyroid cancer cells. In conclusion, our findings suggest that MAPK8IP1P2 may serve as a potential biomarker to predict lymphatic metastasis in thyroid cancer, or a potential therapeutic target in lymphatic metastatic thyroid cancer.

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Activating Hippo Pathway via Rassf1 by Ursolic Acid Suppresses the Tumorigenesis of Gastric Cancer

Cited by 37 publications

References 53 publications

Association analysis between SNPs in LATS1 and LATS2 and non-cardia gastric cancer

Association analysis between SNPs in LATS1 and LATS2 and non-cardia gastric cancer

RP11-323N12.5 promotes the malignancy and immunosuppression of human gastric cancer by increasing YAP1 transcription

Long Non-Coding RNA MAPK8IP1P2 Inhibits Lymphatic Metastasis of Thyroid Cancer by Activating Hippo Signaling via Sponging miR-146b-3p

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