Downregulation of Hlx Closely Related to the Decreased Expressions of T-bet and Runx3 in Patients with Gastric Cancer May Be Associated with a Pathological Event Leading to the Imbalance of Th1/Th2
T-bet plays an important role in immunoregulation; it induces the differentiation of Th1 together with the homeobox transcription factor gene Hlx. Recent studies show that T-bet and Th1-associated factors are critical in regulating tumor development. However, the contributions of Hlx in the occurrence and development of cancer remain unknown. In this study, the Hlx, T-bet, Runx3, and IFN-γ were measured in PBMC from patients with gastric cancer and the correlation between Hlx and T-bet or IFN-γ was assessed. The expression levels of Hlx, T-bet, and IFN-γwere significantly decreased, and there was a positive correlation between Hlx and T-bet or IFN-γ. In addition, the Runx3 expression was also downregulated with the lower T-bet mRNA level. These results suggested that the decreased Hlx expression was closely associated with T-bet and Runx3 downregulations and may contribute to the development of gastric cancer. 1. Introduction Transcription factors act in concert to induce lineage commitment towards Th1, Th2, Th17, or T regulatory (Treg) cells, and their counter-regulatory mechanisms are shown to be critical for polarization between Th1 and Th2 phenotypes [1–3]. Differentiation of naive T lymphocytes into Th1 cell requires IFN-γ (interferon-gamma) which induces the Th1 transcription factor, T-bet. But IFN-γ just induces initial T-bet expression, late expression of T-bet to be needs accompanied by the upregulation of the transcription factors Runx3 and Hlx (also known as Hlx1, H2.0-like homeobox or HB24), and is required to imprint the Th1 cell for IFN-γ reexpression [4]. As a strong candidate for a tumor suppressor, Runx3, a member of runt-related transcription factors (Runx1, Runx2, and Runx3), has been widely studied in a variety of human cancers [5]. Loss of Runx3 leading to elevated oncogenic activity was found to be a key event in inducing a precancerous state of the stomach. The increase in the level of active p53 protein leads to an inhibition of entry into S-phase or the induction of apoptosis [6]. Thus, the loss or inactivation of p53 results in the loss of cell-cycle arrest or apoptosis after DNA damage or physiologic stresses. This loss, seen in many human cancers, has been proposed to lead to increased genetic instability, increased accumulation of mutations, and ultimately oncogenesis. Interestingly, a number of studies indicate that tumor-derived mutant forms of p53, which are highly expressed in many cancers while losing many of their DNA-damage checkpoint functions function as active transforming genes [7]. These mutant p53 genes serve as
References
[1]
M. M. Khan, S. Chatterjee, V. P. Dwivedi et al., “CD4+ T cell-derived novel peptide Thp5 induces interleukin-4 production in CD4+ T cells to direct T helper 2 cell differentiation,” The Journal of Biological Chemistry, vol. 287, no. 4, pp. 2830–2835, 2012.
[2]
M. Yang, S. Wang, S. Wang et al., “Tat-mediated intracellular delivery of T-bet protein into THP-1 cells can induce Th1-type response,” Immunological Investigations, vol. 37, no. 2, pp. 97–111, 2008.
[3]
A. Sharma, M. Rajappa, A. Satyam, and M. Sharma, “Cytokines (TH1 and TH2) in patients with advanced cervical cancer undergoing neoadjuvant chemoradiation correlation with treatment response,” International Journal of Gynecological Cancer, vol. 19, no. 7, pp. 1269–1275, 2009.
[4]
E. G. Schulz, L. Mariani, A. Radbruch, and T. H？fer, “Sequential polarization and imprinting of Type 1 T helper lymphocytes by interferon-γ and interleukin-12,” Immunity, vol. 30, no. 5, pp. 673–683, 2009.
[5]
K. Blyth, E. R. Cameron, and J. C. Neil, “The RUNX genes: gain or loss of function in cancer,” Nature Reviews Cancer, vol. 5, no. 5, pp. 376–387, 2005.
[6]
D. Reisman, P. Takahashi, A. Polson, and K. Boggs, “Transcriptional regulation of the p53 tumor suppressor gene in S-phase of the cell-cycle and the cellular response to DNA damage,” Biochemistry Research International, vol. 2012, Article ID 808934, 2012.
[7]
M. B. Kastan and E. Berkovich, “p53: a two-faced cancer gene,” Nature Cell Biology, vol. 9, no. 5, p. 489, 2007.
[8]
A. M. Goh, C. R. Coffill, and D. P. Lane, “The role of mutant p53 in human cancer,” Journal of Pathology, vol. 223, no. 2, pp. 116–126, 2011.
[9]
H. Qingzhen, T. Jia, W. Shengjun et al., “Corynebacterium pyruviciproducens promotes the production of ovalbumin specific antibody via stimulating dendritic cell differentiation and up-regulating Th2 biased immune response,” Vaccine, vol. 30, no. 6, pp. 1115–1123, 2012.
[10]
P. Yang, G. Qiu, S. Wang et al., “The mutations of Th1 cell-specific T-box transcription factor may be associated with a predominant Th2 phenotype in gastric cancers,” International Journal of Immunogenetics, vol. 37, no. 2, pp. 111–115, 2010.
[11]
K. Suttner, P. Rosenstiel, M. Depner et al., “TBX21 gene variants increase childhood asthma risk in combination with HLX1 variants,” Journal of Allergy and Clinical Immunology, vol. 123, no. 5, pp. 1062–1068, 2009.
[12]
G. Rajaraman, P. Murthi, B. Leo, et al., “Homeobox gene HLX1 is a regulator of colony stimulating factor-1 dependent trophoblast cell proliferation,” Placenta, vol. 28, no. 10, pp. 991–998, 2007.
[13]
M. Martinez, N. Ono, M. Planutiene, K. Planutis, E. L. Nelson, and R. F. Holcombe, “Granulocyte-macrophage stimulating factor (GM-CSF) increases circulating dendritic cells but does not abrogate suppression of adaptive cellular immunity in patients with metastatic colorectal cancer receiving chemotherapy,” Cancer Cell International, vol. 12, no. 1, p. 2, 2012.
[14]
D. J. Klinke II, N. Cheng, and E. Chambers, “Quantifying crosstalk among interferon- , interleukin-12, and tumor necrosis factor signaling pathways within a TH1 cell model,” Science Signaling, vol. 5, no. 220, article ra32, 2012.
[15]
B. H. Li, S. B. Xu, F. Li et al., “Stat6 activity-related Th2 cytokine profile and tumor growth advantage of human colorectal cancer cells in vitro and in vivo,” Cell Signaling, vol. 24, no. 3, pp. 718–725, 2012.
[16]
K. J？hrens, M. Dietel, and I. Anagnostopoulos, “Three different expression patterns of T-bet in angioimmunoblastic T-cell lymphoma,” Leukemia Lymphoma, vol. 53, no. 1, pp. 152–155, 2012.
[17]
L. Hou, E. M. El-Omar, J. Chen et al., “Polymorphisms in Th1-type cell-mediated response genes and risk of gastric cancer,” Carcinogenesis, vol. 28, no. 1, pp. 118–123, 2007.
[18]
J. Zhu, B. Min, J. Hu-Li et al., “Conditional deletion of Gata3 shows its essential function in TH1-TH2 responses,” Nature Immunology, vol. 5, no. 11, pp. 1157–1165, 2004.
[19]
S. J. Liu, J. P. Tsai, C. R. Shen et al., “Induction of a distinct CD8 Tnc17 subset by transforming growth factor-β and interleukin-6,” Journal of Leukocyte Biology, vol. 82, no. 2, pp. 354–360, 2007.
[20]
J. Testori, B. Schweighofer, I. Helfrich et al., “The VEGF-regulated transcription factor HLX controls the expression of guidance cues and negatively regulates sprouting of endothelial cells,” Blood, vol. 117, no. 9, pp. 2735–2744, 2011.
[21]
T. D. Kim, S. Oh, S. Shin, and R. Janknecht, “Regulation of tumor suppressor p53 and HCT116 cell physiology by histone demethylase JMJD2D/KDM4D,” PLoS One, vol. 7, no. 4, article e34618, 2012.
[22]
R. L. Dusek, J. L. Bascom, H. Vogel et al., “Deficiency of the p53/p63 target Perp alters mammary gland homeostasis and promotes cancer,” Breast Cancer Research, vol. 14, no. 2, article R65, 2012.
[23]
P. N. Le Sou？f, “Gene-environmental interaction in the development of atopic asthma: new developments,” Current Opinion in Allergy and Clinical Immunology, vol. 9, no. 2, pp. 123–127, 2009.
