The function of homeobox genes and lncRNAs in cancer

Wang, Yingchao; Dang, Yuan; Liu, Jingfeng; Ouyang, Xiaojuan

doi:10.3892/ol.2016.4901

Cited by 39 publications

(26 citation statements)

References 104 publications

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“…Thus, the actions of HOTTIP and HOTAIR to HOXA13 and HOXD10 loci are cis and trans , respectively . However, to our knowledge no common targets, which are regulated by both lncRNAs are present previously and the mechanistic regulation of the lncRNAs‐HOX axis on their target remains to be clarified .…”

Section: Introductionmentioning

confidence: 89%

Reprogramming Antagonizes the Oncogenicity of HOXA13-Long Noncoding RNA HOTTIP Axis in Gastric Cancer Cells

Wang

Liu

et al. 2017

Stem Cells

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Reprogramming of cancer cells into induced pluripotent stem cells (iPSCs) is a compelling idea for inhibiting oncogenesis, especially through modulation of homeobox proteins in this reprogramming process. We examined the role of various long noncoding RNAs (lncRNAs)-homeobox protein HOXA13 axis on the switching of the oncogenic function of bone morphogenetic protein 7 (BMP7), which is significantly lost in the gastric cancer cell derived iPS-like cells (iPSLCs). BMP7 promoter activation occurred through the corecruitment of HOXA13, mixed-lineage leukemia 1 lysine N-methyltransferase, WD repeat-containing protein 5, and lncRNA HoxA transcript at the distal tip (HOTTIP) to commit the epigenetic changes to the trimethylation of lysine 4 on histone H3 in cancer cells. By contrast, HOXA13 inhibited BMP7 expression in iPSLCs via the corecruitment of HOXA13, enhancer of zeste homolog 2, Jumonji and AT rich interactive domain 2, and lncRNA HoxA transcript antisense RNA (HOTAIR) to various cis-element of the BMP7 promoter. Knockdown experiments demonstrated that HOTTIP contributed positively, but HOTAIR regulated negatively to HOXA13-mediated BMP7 expression in cancer cells and iPSLCs, respectively. These findings indicate that the recruitment of HOXA13-HOTTIP and HOXA13-HOTAIR to different sites in the BMP7 promoter is crucial for the oncogenic fate of human gastric cells. Reprogramming with octamer-binding protein 4 and Jun dimerization protein 2 can inhibit tumorigenesis by switching off BMP7. STEM CELLS 2017;35:2115-2128 SIGNIFICANCE STATEMENTReprogramming of the gastric cancer cells is a challengeable approach for therapeutic use. Here we report the successful reprogramming of the human gastric cells into induced pluripotent stem cell-like cells (iPSLCs) using Jun dimerization protein 2 (JDP2) and octamer-binding protein 4 (OCT4). The oncogenic function of Bone morphogenetic protein 7 (BMP7) is switched by long noncoding RNA-HOXA13 axis and lost in the gastric cancer cell-derived iPSLCs. The recruitment of HOXA13-HoxA transcript at the distal tip (HOTTIP) complex and HOXA13-HoxA transcript antisense RNA (HOTAIR) complex to different sites in the BMP7 promoter is critical for the oncogenic fate of human gastric cells. Thus, reprogramming with OCT4 and JDP2 can inhibit tumorigenic function by switching off BMP7.

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Section: Introductionmentioning

confidence: 89%

Reprogramming Antagonizes the Oncogenicity of HOXA13-Long Noncoding RNA HOTTIP Axis in Gastric Cancer Cells

Wang

Liu

et al. 2017

Stem Cells

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“…In humans, HOX genes are organized into 4 clusters (A, B, C, and D), which are situated on various chromosomes [18]. Interestingly, several lncRNAs associated with HOX genomic regions can partake in the regulation of HOX genes and work together in their functions [19]. HOTAIR lncRNA is transcribed from the antisense strand of the HoxC gene, which is located on chromosome 12q13.13 between the HoxC11 and HoxC12 genes [20] and one of the most significant administrative RNAs in human cells.…”

Section: Introductionmentioning

confidence: 99%

Long non-coding RNA HOTAIR and HOTTIP as potential biomarkers for hepatitis C virus genotype 4-induced hepatocellular carcinoma

Roshdy

Farag

El‐Ahwany

et al. 2020

Egypt J Med Hum Genet

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Background: Long non-coding RNAs (lncRNAs) homeobox (Hox) transcript antisense intergenic RNA (HOTAIR) and HOXA transcript at the distal tip (HOTTIP) have been suggested to be implicated in liver cancer tumorigenesis and progression; however, little is known about the role of the plasma HOTAIR and HOTTIP in liver cancer diagnosis and prognosis. The current study aimed at measuring the plasma levels of long non-coding RNAs (HOTAIR and HOTTIP) expression in chronic liver disease (CLD) due to HCV genotype 4 infection with/without cirrhosis and HCC patients in an attempt to evaluate the potential benefits of these new circulating as non-invasive diagnostic biomarkers and a novel therapeutic strategy for liver cirrhosis and carcinogenesis of Egyptian patients. Hundred subjects were included in this study, divided into two groups; group I (50 patients) were classified into subgroup Ia (CLD without cirrhosis, n = 25) and subgroup Ib (CLD with cirrhosis, n = 25), group II (CLD patients with HCC, n = 25), and control (healthy volunteer, n = 25). The expression of lncRNAs (HOTAIR and HOTTIP) genes was analyzed by real-time PCR. Results: LncRNAs (HOTAIR and HOTTIP) showed upregulation in all diseased groups, which was in consistent with the progression of the disease toward the HCC stage. In addition, HOTAIR and HOTTIP showed a diagnostic ability to discriminate between cases of cirrhosis and HCC compared with healthy control (p < 0.001), while HOTAIR and HOTTIP did not show a discrimination significant differences between cirrhotic cases and non-cirrhotic cases. By using receiver operating characteristic curve (ROC) analysis, it was found that LncRNAs (HOTAIR and HOTTIP) could diagnose liver cancer with 64.0% sensitivity and 86.0% specificity and 48.0% sensitivity and 88.0% specificity. Furthermore, both genes can be considered as the predictor and prognostic parameters for cirrhosis (OR = 1.111, p = 0.05) and (OR = 1.07, p = 0.05) respectively, and HCC (OR = 1.047, p = 0.01) and (OR = 1.05, p = 0.003). The increased HOTAIR and HOTTIP expression were associated with advanced tumor stages and higher grades. Conclusion: These results strongly prompt us that HOTAIR and HOTTIP genes can be used as non-invasive prognostic biomarkers and new therapeutic targets for HCV genotype 4-induced HCC.

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“…However, LHX3 was found as an oncogene in the present study. After systematic retrieval of literature, genes of the same family with different (tumor suppressive or oncogenic) roles are a common phenomenon in cancer development, such as the well known SOX and HOX family gene (30–32). We then used The UCSC Cancer Genomics Browser () to analyze the gene expression in cancer and normal lung tissues.…”

Section: Discussionmentioning

confidence: 99%

LHX3 is an early stage and radiosensitivity prognostic biomarker in lung adenocarcinoma

Lin

Wang

et al. 2017

Oncology Reports

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Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. We previously identified LHX3 as a new preferentially expressed gene in NSCLC. In the present study, we sought to determine its expression, the clinical relevance and the functional roles in NSCLC. LHX3 expression is sharply increased in carcinoma tissues compared to non-carcinoma tissues. Relational analysis reveals a significant association between LHX3 expression and clinical stage (n=172, P=0.032) or radiotherapy (n=167, P=0.022) of patients. LHX3 expression is much higher in the patients at advanced stages (stage III–IV) than in the patients at early stages (stage I–II, P=0.0304), and LHX3 expression is remarkably increased in the patients with radiotherapy treatment (P=0.0002). Survival analyses indicate that LHX3 is associated with unfavorable survival (n=180, P=0.002) and represents an independent prognostic factor [hazard ratio (HR)=1.834, P=0.004] of the NSCLC patients. Furthermore, LHX3 is associated with unfavorable overall survival (n=866, P=0.004) and represents an independent prognostic factor (HR=2.36, P=0.000) in lung adenocarcinoma (ADC) patients, but is not associated with overall survival of squamous cell carcinoma (SCC) patients (n=524, P=0.27). Further analyses found that LHX3 is an early-stage (n=94, P=0.003) and radiosensitivity (n=45, P=0.002) prognostic factor in ADC patients. The patients without radiotherapy have a significantly prolonged survival compared to those with radiotherapy (P=0.0069). Further functional studies show that forced expression of LHX3 in lung cancer cells obviously promotes cell proliferation and invasion, whereas inhibits cell apoptosis. In summary, LHX3 is an early-stage and radiosensitivity prognostic biomarker, and a novel potential oncogene in ADC.

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The function of homeobox genes and lncRNAs in cancer

Cited by 39 publications

References 104 publications

Reprogramming Antagonizes the Oncogenicity of HOXA13-Long Noncoding RNA HOTTIP Axis in Gastric Cancer Cells

Reprogramming Antagonizes the Oncogenicity of HOXA13-Long Noncoding RNA HOTTIP Axis in Gastric Cancer Cells

Long non-coding RNA HOTAIR and HOTTIP as potential biomarkers for hepatitis C virus genotype 4-induced hepatocellular carcinoma

LHX3 is an early stage and radiosensitivity prognostic biomarker in lung adenocarcinoma

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