Role of HOX Genes in Stem Cell Differentiation and Cancer

Bhatlekar, Seema; Fields, Jeremy Z.; Boman, Bruce M.

doi:10.1155/2018/3569493

Cited by 143 publications

(134 citation statements)

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“…It is possible that normal tissues may not be truly normal and could have altered HOXA10 expression or there are distinct but context‐dependent roles for HOXA10 function. Aberrant and context‐dependent roles other HOX genes in the development of cancers has been observed . Further evidence for possible duplicitous roles of HOXA10 is supported by the fact that a portion of high HOXA10‐expressing PCa experienced longer time to BCR.…”

Section: Discussionmentioning

confidence: 97%

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HOXA10 expression profiling in prostate cancer

et al. 2019

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Background HOX genes encode transcription factors that play key roles in modulating normal tissue morphogenesis, differentiation and homeostasis. Disruption of normal HOX gene expression occurs frequently in human cancers and is associated with both tumor promoting and suppressing activities. Among these is, HOXA10, a pleiotropic gene that is critical for normal prostate development. In this study we characterized HOXA10 expression in human and mouse PCa to gain insights into its clinical significance. Methods A meta‐analysis of HOXA10 mRNA expression was carried out across several publicly available data sets. Expression of HOXA10 protein expression was assessed by immunohistochemistry (IHC) using human radical prostatectomy (RP) cases. We correlated HOXA10 expression to clinicopathological features and investigated its relationship to biochemical recurrence (BCR) after RP by the Kaplan‐Meier method. HOXA10 mRNA and IHC protein expression was also examined in a mouse model of Pten‐null PCa. Results A meta‐analysis of HOXA10 gene expression indicated dysregulated expression of HOXA10 in human PCa. IHC profiling of HOXA10 revealed inverse correlations between HOXA10 expression and Gleason pattern, Gleason score, and pathological stage (P < 0.01). Patients with low expression profiles of HOXA10 were associated with a higher risk of BCR, (OR, 3.54; 95%CI, 1.21‐16.14; P = 0.049) whereas patients with high HOXA10 expression experienced longer times to BCR (P = 0.045). However, HOXA10 was not an independent predictor of BCR (OR, 1.52; 95%CI, 0.42‐5.54; P = 0.52). Evaluation of expression patterns of HOXA10 in mouse prostate tumors mimicked that of humans. Conclusions Our findings show that HOXA10 expression is inversely associated with tumor differentiation and high HOXA10 expression is associated with improved BCR‐free survival. This study provides human and mouse evidence to suggest tumor suppressive roles for HOXA10 in the context of prostate cancer.

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Section: Discussionmentioning

confidence: 97%

“…Aberrant and context-dependent roles other HOX genes in the development of cancers has been observed. 34 Further evidence for possible duplicitous roles of HOXA10 is supported by the fact that a portion of high HOXA10-expressing PCa experienced longer time to BCR.…”

Section: Reduced Hoxa10 Is Observed In a Mouse Ptennull Prostate Camentioning

confidence: 99%

HOXA10 expression profiling in prostate cancer

et al. 2019

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“…The c‐MYC gene is associated with cell proliferation, and it has been shown that the association between p53 and c‐myc may be fundamental for chemotherapy in colon carcinoma cells (Arango et al ., 2001). The SRC and HOXB3 genes are associated with proliferation, migration, and angiogenesis and may contribute to the metastatic process (Chikara et al ., 2017; Bahtlekar et al , 2018). Downregulation of the SMAD4 gene (2.85‐, 4.16‐, and 3.84‐fold downregulation for 5, 10, and 50 M, respectively) was also observed after silibinin treatment in wild‐type cells only.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of urinary bladder cancer cell proliferation by silibinin

Barros

Lima

Almeida

et al. 2020

Environ and Mol Mutagen

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Silibinin, a natural compound extracted from milk thistle, has demonstrated antitumor properties in urinary bladder cancer cells; however, the role of TP53 gene in these effects is unclear. In order to better understand the molecular and antiproliferative mechanisms of this compound, urinary bladder cancer cells with different TP53 gene status, RT4 (low-grade tumor, wild TP53 gene), 5637 (high-grade tumor, Grade 2, mutated TP53 gene), and T24 (high-grade tumor, Grade 3, mutated TP53 gene) were treated with several concentrations of silibinin (1, 5, 10, 50, 100, and 150 μM). Cytotoxicity, prooxidant effect, morphological changes, cell migration, cell cycle progression, global methylation profile, and relative expression of HOXB3, c-MYC, PLK1, SMAD4, SRC, HAT, HDAC, and RASSF1A genes were evaluated. The silibinin presented cytotoxic and prooxidant effects in the three cell lines. In mutated TP53 cells, significant interference in cell migration and cell cycle arrest at the G2/M phase was observed. Additionally, silibinin induced global DNA hypomethylation in the highest grade tumor cells. For wild-type TP53 cells, a sub-G1 apoptotic population was present. Furthermore, there was modulation of gene expression responsible for cell growth (SMAD and c-MYC), migration (SRC), cell cycle kinetics (PLK1), angiogenesis (HOXB3), and of genes associated with epigenetic events such as DNA acetylation (HAT) and deacetylation (HDAC).In conclusion, the silibinin inhibited the urinary bladder tumor cell proliferation independently of TP53 status; however, cell cycle effects, gene expression changes, and alteration of cell migration are dependent on TP53 status.

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“…In the past years, HOX genes emerged as transcriptional regulators responsible for embryogenesis and were involved in the development of various cancers . As an essential part of HOXA family genes, HOXA10 expression was crucial for ensuring normal development and differentiation of hematopoietic stem cells . Moreover, emerging evidence indicated that upregulation of HOXA10 was associated with different cancer types …”

Section: Discussionmentioning

confidence: 99%

“…4 As an essential part of HOXA family genes, HOXA10 expression was crucial for ensuring normal development and differentiation of hematopoietic stem cells. 25 Moreover, emerging evidence indicated that upregulation of HOXA10 was associated with different cancer types. 26,27 In our present study, we demonstrated that HOXA10 was elevated in GC tissues.…”

Section: Discussionmentioning

confidence: 99%

HOXA10 induces BCL2 expression, inhibits apoptosis, and promotes cell proliferation in gastric cancer

et al. 2019

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Homeobox A10 (HOXA10) has been implicated critical for the promotion of carcinogenesis, but the underlying mechanism between HOXA10 and malignant gastric cancer (GC) phenotype remains elusive. In the present study, we analyzed and validated that HOXA10 and BCL2 expressions were elevated both at the mRNA and protein levels in GC tissues. Upregulated HOXA10 promoted GC cell proliferation with reduced apoptosis in vitro and accelerated GC tumor growth in vivo. Bioinformatics analysis and quantitative real‐time polymerase chain reaction (qRT‐PCR) experiment inferred that HOXA10 might upregulate the expression of BCL2. By performing western blot, chromatin immunoprecipitation and quantitative PCR (ChIP‐qPCR), and rescue experiment, we found that HOXA10 might bind to BCL2 promoter region, induce its expression, and thus inhibit intrinsic apoptosis pathway. Moreover, higher expression of HOXA10 and BCL2 predicted poor overall survival (OS) in GC patients. In summary, our study indicated that HOXA10 was upregulated in GC, and that HOXA10 might promote cell proliferation by elevating BCL2 expression and inhibiting apoptosis.

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Role of HOX Genes in Stem Cell Differentiation and Cancer

Cited by 143 publications

References 100 publications

HOXA10 expression profiling in prostate cancer

HOXA10 expression profiling in prostate cancer

Inhibition of urinary bladder cancer cell proliferation by silibinin

HOXA10 induces BCL2 expression, inhibits apoptosis, and promotes cell proliferation in gastric cancer

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