HOTTIP and HOXA13 are oncogenes associated with gastric cancer progression
- Authors:
- Published online on: April 13, 2016 https://doi.org/10.3892/or.2016.4743
- Pages: 3577-3585
Abstract
Introduction
Gastric cancer is the second leading cause of cancer-related death worldwide (1). For most patients, gastric cancer is only diagnosed at the advanced stages with poor prognosis (2,3). Gastric carcinogenesis is known as a multistep process involving a series of epigenetic and genetic alterations (4–11). The mechanism of gastric carcinogenesis has not yet been fully elucidated and more studies are needed to search for novel molecules which are involved in the process.
Long non-coding RNAs (lncRNAs) are RNA transcripts which are >200 bp in length and do not encode for a protein (12,13). Studies suggest that lncRNAs constitute an important component of tumor biology (14–18). Most lncRNAs play a functional role in gene expression by targeting either genomically local or distant genes (19–21). Evidence suggests that lncRNAs play essential roles in tumorigenesis (14,22–24) and cancer progression (15,25–27) by acting as either oncogenes or tumor suppressors.
The regulation of HOX genes by lncRNAs is gaining great interest in developmental biology research. HOX genes are highly conserved at the genomic level. The proteins which HOX genes encode are master regulators of embryonic development and continue to be expressed throughout adulthood in various tissues. HOXA transcript at the distal tip (HOTTIP) is at the 5′ end of the HOXA cluster and upregulates the expression of 5′ HOXA genes by binding the adaptor protein WDR5 and targeting the WDR5/MLL complex (28). Evidence suggests that HOTTIP and homeobox protein Hox-A13 (HOXA13) are both upregulated and associated with progression and poor survival of hepatocellular carcinoma (29). Moreover, the expression of HOTTIP and HOXA13 showed a high correlation in hepatocellular carcinoma (29). The role of HOTTIP has also been investigated in pancreatic (30,31) and lung cancer, and tongue squamous cell carcinoma (32,33). For example, HOTTIP promoted disease progression and gemcitabine resistance by regulating HOXA13 in pancreatic cancer (30). In addition, HOTTIP promoted tumor growth and inhibited cell apoptosis in lung cancer (32). In addition, HOTTIP was found to be highly expressed and correlated with the progression of tongue squamous cell carcinoma (33). However, the role of HOTTIP in gastric cancer has never been reported.
In the present study, we investigated the expression of HOTTIP in gastric tissues and the function of HOTTIP in gastric cancer cells, with the aim of elucidating the mechanisms of gastric carcinogenesis and progression.
Materials and methods
Cell culture
Human immortal gastric epithelial cell line GES-1 and human gastric cancer cell lines SGC7901, MKN28, MKN45 and MGC803 were obtained from the Cell Resource Center, Shanghai Institute of Biochemistry and Cell Biology at the Chinese Academy of Sciences. Cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS) (both from Gibco, Carlsbad, CA, USA) at 37°C in a humidified incubator containing 5% carbon dioxide.
Small interfering RNA (siRNA) transfection
The siRNA oligonucleotides targeting HOTTIP, HOXA13 and the negative control were obtained from GenePharma Co., Ltd. (Shanghai, China). Transfection of the oligonucleotides was conducted with X-tremeGENE siRNA transfection reagent (Roche Molecular Biochemicals, Indianapolis, IN, USA) according to the manufacturer's instructions. The sequences of siRNAs used in the present study are listed in Table I.
RNA extraction and quantitative real-time PCR
Total RNA was extracted from cells or tissues using TRIzol reagent (Invitrogen, Carlsbad, CA, USA) according to the manufacturer's instructions. The cDNA was synthesized using the RevertAid First Strand cDNA Synthesis kit (Thermo Fisher Scientific, Inc., Rockford, IL, USA). Quantitative real-time PCR was performed using a SYBR Premix Ex Taq™ II (Takara Biotechnology Co., Ltd., Dalian, China) on a Bio-Rad CFX-96 Real-Time PCR system. GAPDH was used as an internal control. The sequences of the primers are listed in Table II. All qRT-PCR reactions were performed in triplicate.
Cell proliferation and colony formation assays
Cell proliferation was measured by the Cell Counting Kit-8 (CCK-8) assay (7Sea Biotech Co., Ltd., Shanghai, China). Cells transfected with siRNA were seeded and cultured into 96-well plates (3×103 cells/well) in 100 µl medium. At different time points indicated in the figures, 10 µl CCK-8 solution was added into the medium and further incubated with the cells for 3 h. The optical density (OD) was measured using a microplate reader at 450 nm. The CCK-8 assays were performed in triplicate.
For colony formation assay, cells transfected with different siRNAs were seeded into 6-well plates at 300 cells/well. After 14 days of incubation, cells were fixed with methyl alcohol and stained with 0.5% crystal violet. The number of colonies (≥50 cells/colony) was counted. Each experiment was performed in triplicate.
Cell migration and invasion assays
For migration assays, 5×104 cells were plated in the top chamber with a non-coated membrane (24-well insert; pore size, 8-µm; Corning, Corning, NY, USA). For invasion assays, 1.5×105 cells were plated in the top chamber with a Matrigel-coated membrane (24-well insert; pore size, 8-µm; Corning). Medium without serum was used in the top chamber in both assays. Medium with 10% FBS was added to the lower chamber. After incubation for 24 h (migration assay) or 48 h (invasion assay), respectively, the cells that did not migrate or invade through the pores were removed using a cotton swab. Cells on the lower surface of the membrane were fixed with 4% paraformaldehyde and stained with 0.1% crystal violet. The number of migrated or invaded cells was counted. Each experiment was performed in triplicate.
Western blot analysis
Cells were lysed with RIPA buffer containing complete protease inhibitor mixture (Roche Molecular Biochemicals). Proteins were separated by dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to nitrocellulose membranes (Pall Life Sciences, Ann Arbor, MI, USA). The membranes were blocked in 5% non-fat milk and blotted with antibodies against GAPDH (1:2,000) and HOXA13 (1:200) (both from Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA), respectively. The membranes were then incubated with horseradish peroxidase-conjugated secondary antibodies and visualized with an enhanced chemiluminescence reagent.
Tissue samples
A total of 50 paired gastric tissue samples (cancer lesions and adjacent non-tumor mucosae) of gastric cancer patients were obtained from the Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University between June 2013 and February 2014. All patients did not receive chemotherapy or radiotherapy prior to surgery. All samples were collected in the same manner. The samples were immediately frozen in liquid nitrogen and stored at −80°C until they were used. Informed consent was obtained from each patient before the surgery. The present study was approved by the Research Ethics Committee of Xi'an Jiaotong University.
Statistical analysis
Statistical analysis was performed using IBM SPSS Statistics software (IBM Corp., Armonk, NY, USA). Student's t-test for parametric variables was used. Spearman test was used to establish the correlation between HOTTIP and HOXA13. Data are presented as mean ± SEM unless otherwise indicated. All P-values were determined from two-sided tests, and statistical significance was determined based on a P-value of 0.05.
Results
HOTTIP is upregulated in gastric cancer cells and downregulation of HOTTIP inhibits cancer cell growth
To determine the role of HOTTIP in gastric cancer, we first investigated the expression of HOTTIP in the GES-1, MKN28, MGC803, SGC7901 and MKN45 cell lines. In addition, we found that HOTTIP was upregulated in gastric cancer cell lines compared with that noted in the GES-1 cells (Fig. 1A). Then, we investigated the effect of HOTTIP on cell growth by downregulating HOTTIP expression in the SGC7901 and MKN45 cells. Efficiency of HOTTIP knockdown in the SGC7901 and MKN45 cells by three specific siRNAs was confirmed by qRT-PCR and siHOTTIP #1 was used in the following experiments (Fig. 1B). Knockdown of HOTTIP inhibited cell proliferation in the SGC7901 and MKN45 cells (Fig. 1C). The inhibition of cell growth by HOTTIP knockdown was further confirmed by colony formation assay. Downregulation of HOTTIP decreased colony numbers in the SGC7901 and MKN45 cells (Fig. 1D1 and D2). These results suggest that HOTTIP plays a growth-promoting role in gastric cancer cells.
Downregulation of HOTTIP inhibits cell migration and invasion in gastric cancer
We next investigated the effect of HOTTIP on the migration and invasion of SGC7901 and MKN45 cells. Downregulation of HOTTIP led to a 2- to 3-fold reduction in the migratory and invasive capabilities of the SGC7901 cells (Fig. 2A1 and A2). Similar results were observed in the MKN45 cells with decreased expression of HOTTIP (Fig. 2B1 and B2). These results suggest that HOTTIP promotes both migration and invasion of gastric cancer cells.
Downregulation of HOTTIP leads to decreased HOXA13 expression in gastric cancer cells
HOTTIP knockdown was previously found to lead to a reduction in HOXA gene expression in primary human fibroblasts (28), hepatocellular carcinoma (29) and pancreatic cancer cells (30,31). To ascertain whether HOTTIP exhibits a similar function in gastric cancer cells, we measured the expression of several HOXA genes (HOXA13, HOXA11, HOXA10 and HOXA9) in the SGC7901 cells treated with siHOTTIP #1. Downregulation of HOTTIP led to different degrees of decrease in the expression levels of these genes, among which HOXA13 expression was decreased the most (Fig. 3A). Downregulation of HOXA13 expression was further confirmed in MKN45 cells by qRT-PCR (Fig. 3A). Knockdown of HOTTIP inhibited the HOXA13 protein level in the SGC7901 and MKN45 cells (Fig. 3B). These results suggest that HOTTIP regulates HOXA13 expression in gastric cancer cells.
HOXA13 is involved in HOTTIP-induced malignant phenotypes of gastric cancer cells
We investigated the expression of HOXA13 in the GES-1 and gastric cancer cell lines. HOXA13 was upregulated in the gastric cancer cell lines compared with GES-1, which was similar to the HOTTIP expression pattern (Fig. 4A). To investigate the role of HOXA13 in gastric cancer, three specific siRNAs against HOXA13 were used to inhibit HOXA13 mRNA expression in the SGC7901 and MKN45 cells. siHOXA13 #2 showed most significant knockdown efficiency and was used in the following experiments (Fig. 4B). siHOXA13 #2 led to a clear reduction in the protein level of HOXA13 (Fig. 4C).
Knockdown of HOXA13 also inhibited cell growth (Fig. 5A and B), migration and invasion (Fig. 5C) in the SGC7901 and MKN45 cells, which resembled the inhibitory effects of HOTTIP knockdown. These results indicate that HOXA13 was involved in HOTTIP-induced malignant phenotypes of gastric cancer cells.
HOTTIP and HOXA13 are both upregulated in gastric cancer
To further understand the relationship between HOTTIP and HOXA13 in gastric cancer, we investigated HOTTIP and HOXA13 expression levels in 50 pairs of primary gastric cancer tissues and their counterpart non-tumorous tissues by qRT-PCR. The results showed that HOTTIP and HOXA13 were both markedly upregulated in the gastric cancer tissues when compared with these levels in the non-tumorous tissues (Fig. 6A and B), which were consistent with the expression patterns of HOTTIP and HOXA13 in the gastric cancer cells. Correlations between the HOTTIP or HOXA13 expression levels and clinicopathologic characteristics of gastric cancer are summarized in Tables III or IV, respectively. The data revealed that expression levels of HOTTIP and HOXA13 were both higher in gastric cancer which was poorly differentiated (P<0.05), at advanced TNM stages (P<0.05) and showed lymph node metastasis (P<0.01). Spearman analyses indicated that HOTTIP and HOXA13 had a positive correlation both in non-tumor mucosae (Fig. 6C) and cancer lesions (Fig. 6D). These results suggest that HOTTIP and HOXA13 are highly correlated and associated with gastric cancer progression.
 | Table IIIRelationship between HOTTIP expression and clinicopathological parameters in the primary gastric cancer cases. |
| Table IVRelationship between HOXA13 expression and clinicopathological parameters in the primary gastric cancer cases. |
Discussion
In the present study, we found that both HOTTIP and HOXA13 were upregulated in gastric cancer tissues compared with levels in their counterpart non-tumorous tissues. In addition, the expression levels of HOTTIP and HOXA13 were associated with poor differentiation, advanced TNM stages and lymph node metastasis. Moreover, HOTTIP and HOXA13 were highly correlated both in non-tumor mucosae and cancer lesions. Downregulation of HOTTIP inhibited cell growth and invasion. In addition, HOXA13 was involved in HOTTIP-induced malignant phenotypes of gastric cancer cells.
lncRNAs associated with human HOX gene loci have been widely studied in recent years (21,28,34–36). By characterizing the transcriptional landscape of the four human HOX loci, researchers have identified 231 HOX lncRNAs (21). HOTAIR, which was first described in fibroblasts, was found to be located in the HOXC cluster but regulated HOXD cluster genes (21). HOTAIR was also found to serve as a scaffold protein by binding polycomb repressive complex 2 (PRC) with its 5′ domain and the LSD1/CoREST/REST complex with the 3′ domain (37). Unlike HOTAIR, HOTTIP enhanced expression of neighboring HOXA genes particularly HOXA13 (28). Considering the vital role of HOX genes in development and differentiation and their dysregulation-caused tumorigenesis and tumor progression (38–42), it is important to understand the mechanism of HOTTIP in the regulation of HOX gene expression.
Upregulation of HOTTIP and HOXA13 has been reported in various studies. HOTTIP and HOXA13 were both upregulated and highly correlated in hepatocellular carcinoma (29) and pancreatic cancer (31,32). A previous study demonstrated that HOTTIP was upregulated not only in hepatocellular carcinoma tissues, but also in preneoplastic diseases. However, the HOXA13 expression level was specifically increased in hepatocellular carcinoma, indicating that upregulation of HOTTIP preceded that of HOXA13 in hepatocellular carcinogenesis during disease onset (29). HOTTIP was also found to be upregulated in lung cancer (32) and tongue squamous cell carcinoma (33), and involved in the tumor progression in pancreatic cancer (30). The expression level of HOXA13 was also increased and associated with tumor progression in hepatocellular carcinoma (29), pancreatic cancer (30), esophageal squamous cell carcinoma (43) and glioblastoma multiforme (44). A recent study found that HOXA13 expression was higher in cancerous tissues compared with that in their neighboring non-cancerous tissues. Moreover, a higher expression level of HOXA13 was significantly correlated with T and M stages, advanced UICC stage and histological differentiation in gastric cancer based on immunohistochemistry findings (45). In the present study, we also found that HOTTIP and HOXA13 were upregulated in gastric cancer tissues compared with level in their non-tumorous tissues. In addition, the increase in the expression level of these two genes was correlated with cancer tissue poor differentiation, advanced TNM stages and lymph node metastasis. HOTTIP and HOXA13 were positively associated in both non-tumor mucosae and cancer lesions. Our findings suggest that HOTTIP and HOXA13 are likely involved in the tumorigenesis and progression of gastric cancer.
Although we identified upregulation of HOTTIP and HOXA13 in gastric cancer, the roles of HOTTIP and HOXA13 in gastric cancer have never been fully understood. Downregulation of HOTTIP and HOXA13 has been reported to inhibit cell proliferation in liver cancer-derived cells (29). HOTTIP and HOXA13 promoted cell proliferation, migration and invasion in pancreatic cancer (30,31). Moreover, HOTTIP regulated the expression of HOXA13 in hepatocellular carcinoma (29) and pancreatic cancer (30). However, Cheng et al showed that HOTTIP regulated HOX genes including HOXA10, HOXA11, HOXA9 and HOXA1, but not HOXA13 (31). HOXA13 was found to promote cell growth of esophageal squamous cancer cells in vitro and in vivo (43). HOXA13 also promoted cell invasion in vitro and tumor growth in vivo in glioblastoma multiforme (44). In the present study, we firstly identified that HOTTIP and HOXA13 both promoted cell growth and invasiveness in gastric cancer cells. In addition, downregulation of HOTTIP led to decreased HOXA13 expression in gastric cancer cells. The roles of HOTTIP and HOXA13 in gastric cancer cells in vivo warrant further investigation. Taken together, these data indicate that HOTTIP functions as an oncogene by regulating HOXA13 expression in gastric cancer.
In conclusion, our results showed that HOTTIP and HOXA13 were upregulated and associated with poor differentiation, advanced TNM stages and lymph node metastasis in gastric cancer. HOTTIP and HOXA13 were highly correlated in both non-tumor mucosae and cancer lesions. Downregulation of HOTTIP inhibited gastric cancer cell growth and invasiveness through the regulation of HOXA13. These results suggest that the molecular axis of HOTTIP and HOXA13 contributes to gastric cancer progression. Our finding provides a potential novel therapeutic target for gastric cancer treatment.
Acknowledgments
The present study was supported in part by the National Natural Science Foundation of China (no. 81472245).
References
|
Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Takahashi T, Saikawa Y and Kitagawa Y: Gastric cancer: Current status of diagnosis and treatment. Cancers. 5:48–63. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Ajani JA, Bentrem DJ, Besh S, D'Amico TA, Das P, Denlinger C, Fakih MG, Fuchs CS, Gerdes H, Glasgow RE, et al National Comprehensive Cancer Network: Gastric cancer, version 2.2013: Featured updates to the NCCN Guidelines. J Natl Compr Canc Netw. 11:531–546. 2013.PubMed/NCBI | |
|
Zheng L, Wang L, Ajani J and Xie K: Molecular basis of gastric cancer development and progression. Gastric Cancer. 7:61–77. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Tamura G, Yin J, Wang S, Fleisher AS, Zou T, Abraham JM, Kong D, Smolinski KN, Wilson KT, James SP, et al: E-Cadherin gene promoter hypermethylation in primary human gastric carcinomas. J Natl Cancer Inst. 92:569–573. 2000. View Article : Google Scholar : PubMed/NCBI | |
|
Maekita T, Nakazawa K, Mihara M, Nakajima T, Yanaoka K, Iguchi M, Arii K, Kaneda A, Tsukamoto T, Tatematsu M, et al: High levels of aberrant DNA methylation in Helicobacter pylori- infected gastric mucosae and its possible association with gastric cancer risk. Clin Cancer Res. 12:989–995. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Niwa T, Tsukamoto T, Toyoda T, Mori A, Tanaka H, Maekita T, Ichinose M, Tatematsu M and Ushijima T: Inflammatory processes triggered by Helicobacter pylori infection cause aberrant DNA methylation in gastric epithelial cells. Cancer Res. 70:1430–1440. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, Herrera J, Lissowska J, Yuan CC, Rothman N, et al: Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 404:398–402. 2000. View Article : Google Scholar : PubMed/NCBI | |
|
He C, Tu H, Sun L, Xu Q, Gong Y, Jing J, Dong N and Yuan Y: SNP interactions of Helicobacter pylori-related host genes PGC, PTPN11, IL1B, and TLR4 in susceptibility to gastric carcinogenesis. Oncotarget. 6:19017–19026. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Huang TT, Ping YH, Wang AM, Ke CC, Fang WL, Huang KH, Lee HC, Chi CW and Yeh TS: The reciprocal regulation loop of Notch2 pathway and miR-23b in controlling gastric carcinogenesis. Oncotarget. 6:18012–18026. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Shen J, Xiao Z, Wu WK, Wang MH, To KF, Chen Y, Yang W, Li MS, Shin VY, Tong JH, et al: Epigenetic silencing of miR-490-3p reactivates the chromatin remodeler SMARCD1 to promote Helicobacter pylori-induced gastric carcinogenesis. Cancer Res. 75:754–765. 2015. View Article : Google Scholar | |
|
Gibb EA, Brown CJ and Lam WL: The functional role of long non-coding RNA in human carcinomas. Mol Cancer. 10:382011. View Article : Google Scholar : PubMed/NCBI | |
|
Flynn RA and Chang HY: Long noncoding RNAs in cell-fate programming and reprogramming. Cell Stem Cell. 14:752–761. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Huarte M and Rinn JL: Large non-coding RNAs: Missing links in cancer? Hum Mol Genet. 19:R152–R161. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Prensner JR, Iyer MK, Balbin OA, Dhanasekaran SM, Cao Q, Brenner JC, Laxman B, Asangani IA, Grasso CS, Kominsky HD, et al: Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression. Nat Biotechnol. 29:742–749. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Braconi C, Valeri N, Kogure T, Gasparini P, Huang N, Nuovo GJ, Terracciano L, Croce CM and Patel T: Expression and functional role of a transcribed noncoding RNA with an ultraconserved element in hepatocellular carcinoma. Proc Natl Acad Sci USA. 108:786–791. 2011. View Article : Google Scholar : | |
|
Pantoja C, de Los Ríos L, Matheu A, Antequera F and Serrano M: Inactivation of imprinted genes induced by cellular stress and tumorigenesis. Cancer Res. 65:26–33. 2005.PubMed/NCBI | |
|
Yap KL, Li S, Muñoz-Cabello AM, Raguz S, Zeng L, Mujtaba S, Gil J, Walsh MJ and Zhou MM: Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol Cell. 38:662–674. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Brown CJ, Ballabio A, Rupert JL, Lafreniere RG, Grompe M, Tonlorenzi R and Willard HF: A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature. 349:38–44. 1991. View Article : Google Scholar : PubMed/NCBI | |
|
Bartolomei MS, Zemel S and Tilghman SM: Parental imprinting of the mouse H19 gene. Nature. 351:153–155. 1991. View Article : Google Scholar : PubMed/NCBI | |
|
Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, Goodnough LH, Helms JA, Farnham PJ, Segal E, et al: Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell. 129:1311–1323. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Hou P, Zhao Y, Li Z, Yao R, Ma M, Gao Y, Zhao L, Zhang Y, Huang B and Lu J: LincRNA-ROR induces epithelial-to-mesen-chymal transition and contributes to breast cancer tumorigenesis and metastasis. Cell Death Dis. 5:e12872014. View Article : Google Scholar | |
|
Zhang H, Diab A, Fan H, Mani SK, Hullinger R, Merle P and Andrisani O: PLK1 and HOTAIR accelerate proteasomal degradation of SUZ12 and ZNF198 during hepatitis B virus-induced liver carcinogenesis. Cancer Res. 75:2363–2374. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Fan J, Xing Y, Wen X, Jia R, Ni H, He J, Ding X, Pan H, Qian G, Ge S, et al: Long non-coding RNA ROR decoys gene-specific histone methylation to promote tumorigenesis. Genome Biol. 16:1392015. View Article : Google Scholar : PubMed/NCBI | |
|
Barnhill LM, Williams RT, Cohen O, Kim Y, Batova A, Mielke JA, Messer K, Pu M, Bao L, Yu AL, et al: High expression of CAI2, a 9p21-embedded long noncoding RNA, contributes to advanced-stage neuroblastoma. Cancer Res. 74:3753–3763. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Hu Y, Wang J, Qian J, Kong X, Tang J, Wang Y, Chen H, Hong J, Zou W, Chen Y, et al: Long noncoding RNA GAPLINC regulates CD44-dependent cell invasiveness and associates with poor prognosis of gastric cancer. Cancer Res. 74:6890–6902. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang X, Gejman R, Mahta A, Zhong Y, Rice KA, Zhou Y, Cheunsuchon P, Louis DN and Klibanski A: Maternally expressed gene 3, an imprinted noncoding RNA gene, is associated with meningioma pathogenesis and progression. Cancer Res. 70:2350–2358. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Wang KC, Yang YW, Liu B, Sanyal A, Corces-Zimmerman R, Chen Y, Lajoie BR, Protacio A, Flynn RA, Gupta RA, et al: A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature. 472:120–124. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Quagliata L, Matter MS, Piscuoglio S, Arabi L, Ruiz C, Procino A, Kovac M, Moretti F, Makowska Z, Boldanova T, et al: Long noncoding RNA HOTTIP/HOXA13 expression is associated with disease progression and predicts outcome in hepatocellular carcinoma patients. Hepatology. 59:911–923. 2014. View Article : Google Scholar : | |
|
Li Z, Zhao X, Zhou Y, Liu Y, Zhou Q, Ye H, Wang Y, Zeng J, Song Y, Gao W, et al: The long non-coding RNA HOTTIP promotes progression and gemcitabine resistance by regulating HOXA13 in pancreatic cancer. J Transl Med. 13:842015. View Article : Google Scholar : PubMed/NCBI | |
|
Cheng Y, Jutooru I, Chadalapaka G, Corton JC and Safe S: The long non-coding RNA HOTTIP enhances pancreatic cancer cell proliferation, survival and migration. Oncotarget. 6:10840–10852. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Deng HP, Chen L, Fan T, Zhang B, Xu Y and Geng Q: Long non-coding RNA HOTTIP promotes tumor growth and inhibits cell apoptosis in lung cancer. Cell Mol Biol. 61:34–40. 2015.PubMed/NCBI | |
|
Zhang H, Zhao L, Wang YX, Xi M, Liu SL and Luo LL: Long non-coding RNA HOTTIP is correlated with progression and prognosis in tongue squamous cell carcinoma. Tumour Biol. 36:8805–8809. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Maamar H, Cabili MN, Rinn J and Raj A: linc-HOXA1 is a noncoding RNA that represses Hoxa1 transcription in cis. Genes Dev. 27:1260–1271. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang EB, Yin DD, Sun M, Kong R, Liu XH, You LH, Han L, Xia R, Wang KM, Yang JS, et al: P53-regulated long non-coding RNA TUG1 affects cell proliferation in human non-small cell lung cancer, partly through epigenetically regulating HOXB7 expression. Cell Death Dis. 5:e12432014. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang X, Lian Z, Padden C, Gerstein MB, Rozowsky J, Snyder M, Gingeras TR, Kapranov P, Weissman SM and Newburger PE: A myelopoiesis-associated regulatory intergenic noncoding RNA transcript within the human HOXA cluster. Blood. 113:2526–2534. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, Shi Y, Segal E and Chang HY: Long noncoding RNA as modular scaffold of histone modification complexes. Science. 329:689–693. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Liao WT, Jiang D, Yuan J, Cui YM, Shi XW, Chen CM, Bian XW, Deng YJ and Ding YQ: HOXB7 as a prognostic factor and mediator of colorectal cancer progression. Clin Cancer Res. 17:3569–3578. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Cantile M, Pettinato G, Procino A, Feliciello I, Cindolo L and Cillo C: In vivo expression of the whole HOX gene network in human breast cancer. Eur J Cancer. 39:257–264. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Waltregny D, Alami Y, Clausse N, de Leval J and Castronovo V: Overexpression of the homeobox gene HOXC 8 in human prostate cancer correlates with loss of tumor differentiation. Prostate. 50:162–169. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Costa BM, Smith JS, Chen Y, Chen J, Phillips HS, Aldape KD, Zardo G, Nigro J, James CD, Fridlyand J, et al: Reversing HOXA9 oncogene activation by PI3K inhibition: Epigenetic mechanism and prognostic significance in human glioblastoma. Cancer Res. 70:453–462. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Buske C, Feuring-Buske M, Abramovich C, Spiekermann K, Eaves CJ, Coulombel L, Sauvageau G, Hogge DE and Humphries RK: Deregulated expression of HOXB4 enhances the primitive growth activity of human hematopoietic cells. Blood. 100:862–868. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Gu ZD, Shen LY, Wang H, Chen XM, Li Y, Ning T and Chen KN: HOXA13 promotes cancer cell growth and predicts poor survival of patients with esophageal squamous cell carcinoma. Cancer Res. 69:4969–4973. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Duan R, Han L, Wang Q, Wei J, Chen L, Zhang J, Kang C and Wang L: HOXA13 is a potential GBM diagnostic marker and promotes glioma invasion by activating the Wnt and TGF-β pathways. Oncotarget. 6:27778–27793. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Han Y, Tu WW, Wen YG, Li DP, Qiu GQ, Tang HM, Peng ZH and Zhou CZ: Identification and validation that up-expression of HOXA13 is a novel independent prognostic marker of a worse outcome in gastric cancer based on immunohistochemistry. Med Oncol. 30:5642013. View Article : Google Scholar : PubMed/NCBI |
