HOTTIP and HOXA13 are oncogenes associated with gastric cancer progression

Chang, Shuai; Liu, Junsong; Guo, Shaochun; He, Shicai; Qiu, Guanglin; Lü, Jing; Wang, Jin; Fan, Lin; Zhao, Wei; Che, Xiangming

doi:10.3892/or.2016.4743

Cited by 64 publications

(57 citation statements)

References 45 publications

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“…Several studies previously demonstrated that HOXA13 and HOTTIP expression are highly correlated. 20,[50][51][52] Specifically, we reported that HOTTIP activates HOXA13 through epigenetic mechanisms including DNA methylation and histone modifications 22 and Wang et al described that, in the Cs12 gastric cells, HOTTIP knockdown attenuates the recruitment of WDR5 and MLL1 and promotes DNMT3B localization on the HOXA13 promoter. 20 Here by analyzing HOXA13 IHC and HOTTIP ISH on consecutive HCC sections, we showed that HOXA13 and HOTTIP displayed intra-tumor heterogeneous pattern of expression and their concomitant overexpression was found in the same populations of transformed hepatocytes.…”

Section: Discussionmentioning

confidence: 85%

High expression of HOXA13 correlates with poorly differentiated hepatocellular carcinomas and modulates sorafenib response in in vitro models

Quagliata

Quintavalle

Lanzafame

et al. 2018

Laboratory Investigation

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Hepatocellular carcinoma (HCC) represents the fifth and ninth cause of mortality among male and female cancer patients, respectively and typically arises on a background of a cirrhotic liver. HCC develops in a multi-step process, often encompassing chronic liver injury, steatosis and cirrhosis eventually leading to the malignant transformation of hepatocytes. Aberrant expression of the class I homeobox gene family (HOX), a group of genes crucial in embryogenesis, has been reported in a variety of malignancies including solid tumors. Among HOX genes, HOXA13 is most overexpressed in HCC and is known to be directly regulated by the long non-coding RNA HOTTIP. In this study, taking advantage of a tissue microarray containing 305 tissue specimens, we found that HOXA13 protein expression increased monotonically from normal liver to cirrhotic liver to HCC and that HOXA13-positive HCCs were preferentially poorly differentiated and had fewer E-cadherin-positive cells. In two independent cohorts, patients with HOXA13-positive HCC had worse overall survival than those with HOXA13-negative HCC. Using HOXA13 immunohistochemistry and HOTTIP RNA in situ hybridization on consecutive sections of 16 resected HCCs, we demonstrated that HOXA13 and HOTTIP were expressed in the same neoplastic hepatocyte populations. Stable overexpression of HOXA13 in liver cancer cell lines resulted in increased colony formation on soft agar and migration potential as well as reduced sensitivity to sorafenib in vitro. Our results provide compelling evidence of a role for HOXA13 in HCC development and highlight for the first time its ability to modulate response to sorafenib.

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Section: Discussionmentioning

confidence: 85%

High expression of HOXA13 correlates with poorly differentiated hepatocellular carcinomas and modulates sorafenib response in in vitro models

Quagliata

Quintavalle

Lanzafame

et al. 2018

Laboratory Investigation

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“…HOTTIP exhibited lymph node metastasis, and the downregulation of HOTTIP impaired GC cell proliferation, promoted cell apoptosis, and reduced cell invasion and migration in GC. 26,27 HOTTIP prevented glioma progression by sponged endogenous miR-101 and inhibited its activity, further F I G U R E 9 The expression levels of three long noncoding RNAs in gastric cancer tissues resulted in increased ZEB1 expression and promoted the process of EMT. 28 In hepatocellular carcinoma, HOTTIP can be negatively regulated by miR-125b, while miR-192/-204-HOTTIP axis may interrupt HCC glutaminolysis through GLS1 inhibition.…”

Section: Discussionmentioning

confidence: 99%

Identification of functional lncRNAs in gastric cancer by integrative analysis of GEO and TCGA data

Zhang

Jiang

et al. 2019

J of Cellular Biochemistry

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Gastric cancer (GC) is a prevalent malignant cancer of digestive system, identification of novel diagnostic and prognostic biomarkers for GC is urgently demanded. The aim of this study was to determine potential long noncoding RNAs (lncRNAs) associated with the pathogenesis and prognosis of GC. Raw noncoding RNA microarray data (GSE53137, GSE70880, and GSE99417) was downloaded from Gene Expression Omnibus (GEO) database. Differentially expressed genes between GC and adjacent normal gastric tissue samples were screened by an integrated analysis of multiple gene expression profile after gene reannotation and batch normalization. Differentially expressed genes were further confirmed by The Cancer Genome Atlas (TCGA) database. Competing endogenous RNA (ceRNA) network, Gene Ontology term and Kyoto Encyclopedia of Genes and Genomes pathway, survival analysis were extensively applied to identify hub lncRNAs and discover potential biomarkers related to diagnosis and prognosis of GC. In total of 246 integrated differential genes including 15 lncRNAs and 241 messenger RNAs (mRNAs) were obtained after intersections of differential genes between GEO and TCGA database. ceRNA network comprised of three lncRNAs (UCA1, HOTTIP, and HMGA1P4), 26 microRNAs (miRNAs) and 72 mRNAs. Functional analysis revealed that three lncRNAs were mainly dominated in cell cycle and cellular senescence. Survival analysis showed that HMGA1P4 was statistically related to the overall survival rate. For the first time, we identified that HMGA1P4, a target of miR‐301b/miR‐508, is involved in cell cycle and senescence process by regulating CCNA2 in GC. Finally, the expression levels of three lncRNAs were validated to be upregulated in GC tissues. Thus, three lncRNAs including UCA1, HOTTIP, and HMGA1P4 may contribute to GC development and their potential functions might be associated with the prognosis of GC.

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“…It has been confirmed that HOTTIP could directly interact with the Trithorax protein WDR5 inducing an open DNA-chromatin configuration to target WDR5/MLL complexes driving histone H3 lysine 4 trimethylation and thus regulating the transcription of 5′end HOXA locus genes [10]. Interestingly, recent studies also found that there is a positive correlation between the expression of HOTTIP and HOX genes in tumors and normal tissue [14, 30–33]. It has demonstrated that HOTTIP was involved in the cancer progression.…”

Section: Discussionmentioning

confidence: 99%

The prognostic value of long noncoding RNA HOTTIP on clinical outcomes in breast cancer

et al. 2016

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Although a few studies have assessed the prognostic value of long noncoding RNA HOTTIP in patients with malignant tumors, the relationship between HOTTIP and clinical outcome of breast cancer remains elusive. The aim of this study is to explore the prognostic significance of HOTTIP in breast cancer patients. A meta-analysis was performed to involve the eligible studies to investigate the association of HOTTIP expression level with outcome in cancer patients. Pooled hazard ratios (HRs) and 95% confidence interval (CI) of HOTTIP for cancer survival were calculated. Five relevant articles involving 460 patients with various solid carcinomas were included in this meta-analysis. For overall survival, high HOTTIP expression could significantly predict worse outcome with the pooled HR of 2.29 (95 % CI 1.72–3.03, P < 0.00001). Furthermore, Gene Expression Omnibus was performed to evaluate the association of HOTTIP expression with the prognosis in breast cancer patients. It was also found an indication that high HOTTIP expression was associated with worse survival in breast cancer patients by microarray analysis (GSE20711, GSE16446 and GSE9195). Finally, association between HOTTIP levels and clinicopathological factors and prognosis was also analyzed in an independent validation cohort including 100 breast cancer cases. HOTTIP expression was correlated with tumor size (P=0.025), lymph node status (P=0.009) and TNM stage (P=0.0001) in the breast cancer validation cohort. The Kaplan-Meier survival curves indicated that breast cancer patients with high HOTTIP expression had worse overall survival (P=0.0139) and disease-free survival (P=0.0003). Multivariate survival analysis based on the Cox proportional hazards model showed that HOTTP is considered as an independent prognostic factor in breast cancer patients. Together, our combined results suggest that high HOTTIP expression may be serving as an unfavorable prognosis predictor for breast cancer patients.

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HOTTIP and HOXA13 are oncogenes associated with gastric cancer progression

Cited by 64 publications

References 45 publications

High expression of HOXA13 correlates with poorly differentiated hepatocellular carcinomas and modulates sorafenib response in in vitro models

High expression of HOXA13 correlates with poorly differentiated hepatocellular carcinomas and modulates sorafenib response in in vitro models

Identification of functional lncRNAs in gastric cancer by integrative analysis of GEO and TCGA data

The prognostic value of long noncoding RNA HOTTIP on clinical outcomes in breast cancer

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