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Sex-Dependent Regulation of Estrogen Receptor Β in Human Colorectal Cancer Tissue and Its Relationship with Clock Genes and VEGF-A Expression

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Sex-Dependent Regulation of Estrogen Receptor Β in Human Colorectal Cancer Tissue and Its Relationship with Clock Genes and VEGF-A Expression Physiol. Res. 68 (Suppl. 3): S297-S305, 2019 https://doi.org/10.33549/physiolres.934352 Sex-Dependent Regulation of Estrogen Receptor β in Human Colorectal Cancer Tissue and its Relationship With Clock Genes and VEGF-A Expression I. HERICHOVA1*, R. REIS2*, K. HASAKOVA1, M. VICIAN3, M. ZEMAN1 * These authors contributed equally to this work. 1Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovak Republic, 2First Surgery Department, University Hospital, Comenius University Bratislava, Bratislava, Slovak Republic, 3Fourth Surgery Department, University Hospital, Comenius University Bratislava, Bratislava, Slovak Republic Received March 22, 2019 Accepted October 4, 2019 Summary Ilkovicova 6, 842 15 Bratislava, Slovak Republic. E-mail: The incidence of colorectal cancer (CRC) shows a sex-dependent [email protected] difference in humans. The aim of this study was to analyze estrogen receptor β mRNA (ERβ) expression in patients with CRC Introduction with respect to their gender and clinicopathological features. Since cancer progression is accompanied by tumor Epidemiological data clearly indicate that the vascularization, VEGF-A (vascular endothelial growth factor A) incidence of colorectal cancer (CRC) is higher in males transcription was analyzed along with ERβ mRNA. ERβ mRNA than in females. A sex-dependent difference in CRC was also correlated with the expression of clock genes, which are incidence was reported at all anatomic subsites, with the known to influence the cell cycle. ERβ mRNA expression in male-to-female incidence rate ratio increasing females with CRC showed an inverse association with increasing progressively across the colon from the cecum to the tumor staging that was not observed in males. Lower levels of rectum (Murphy et al. 2011, Torre et al. 2012, Siegel ERβ mRNA were observed in females with a higher clinical stage et al. 2015). compared with those with earlier-stage tumors. ERβ mRNA The higher frequency of CRC diagnosis in males expression showed a significant positive correlation with mRNA of is usually attributed to sex steroid hormones. Estrogen in clock genes period 2 and cryptochrome 2 in healthy but not in particular is proposed to exert beneficial effects as cancerous tissue in males. Expression of VEGF-A mRNA showed a hormone-replacement therapy in postmenopausal a negative correlation with ERβ mRNA after splitting of the cohort females and is associated with a reduced risk of CRC and according to gender and nodus involvement. We propose that increased survival (Symer et al. 2018, Nie et al. 2018). In gender differences in ERβ mRNA expression in tumors during the humans, estrogen exerts its effects via estrogen receptor early stages of CRC can partially explain the lower occurrence of α and β (ERα and ERβ, respectively). While CRC in females compared with males. ERα-mediated effects have been studied extensively with respect to several types of cancer (Clocchiatti et al. Key words 2016), the functions of ERβ have not been completely PER2 • CRY1 • CRY2 • Angiogenesis • Circadian elucidated. In the colon, mRNA expression of ERβ is much more abundant than that of ERα (Foley et al. 2000, Corresponding author Kennelly et al. 2008, Williams et al. 2016); therefore, I. Herichova, Department of Animal Physiology and Ethology, effects of estradiol exerted in this tissue are usually Faculty of Natural Sciences, Comenius University Bratislava, attributed to ERβ signaling (Clocchiatti et al. 2016). PHYSIOLOGICAL RESEARCH • ISSN 0862-8408 (print) • ISSN 1802-9973 (online) 2019 Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic Fax +420 241 062 164, e-mail: [email protected], www.biomed.cas.cz/physiolres S298 Herichova et al. Vol. 68 It has been shown that overexpression of ERβ factors BMAL1 (brain and muscle ARNT-Like protein 1) results in inhibition of proliferation and G1 phase cell and CLOCK (circadian locomotor output cycles kaput). cycle arrest in SW480 colon cancer cells. Overexpression Genes involved in basic loop functioning are able to of ERβ was also accompanied by downregulation of Myc mediate oscillations via several regulatory domains proto-oncogene protein expression (Hartman et al. 2009). (including abundantly spread E-box) into the ERβ knockout in mice was associated with decreased transcriptome (Honma 2018). ERβ mRNA expression is apoptosis, an increased proliferation rate and under circadian system control via an E-box present in its abnormalities in the structure of intercellular junctions promoter (Cai et al. 2008), and VEGF shows a rhythmic (Wada-Hiraike et al. 2006). Estrogen has been reported to pattern in several types of in vivo implanted tumor cell play an important role in maintaining the function of the lines and livers of mice (Koyanagi et al. 2003). Clock gastrointestinal epithelial barrier, e.g. by increasing genes have also been shown to influence cell cycle occludin and junctional adhesion molecule-A expression progression (Gaucher et al. 2018). A role for clock genes (Nie et al. 2018). In mice that spontaneously develop in tumor development was supported by a study showing intestinal adenomas because of a nonsense mutation in that polymorphic variants of core clock genes of the the Apc gene, deletion of ERβ leads to an increased size circadian oscillator are associated with several types of and number of adenomas (Giroux et al. 2008), and cancer, including colorectal cancer (Valenzuela et al. a selective ERβ agonist reversed this effect (Giroux et al. 2016). 2011). ERβ mRNA expression has been previously Tumor growth is accompanied by production of shown to exhibit a sex-dependent association with patient novel vascularization, which is stimulated by VEGF survival (Hasakova et al. 2018). A sex-dependent role of (vascular endothelial growth factor) signaling (Claesson- the circadian system in tumorigenesis was demonstrated Welsh and Welsh 2013). Expression of VEGF-A mRNA in a study pointing out different survival rates in males was increased in colorectal carcinoma compared with and females depending on administration of normal mucosa, and higher levels of VEGF-A mRNA chronomodulated chemotherapy (Giacchetti et al. 2012). were observed in tumors with lymph node metastases Therefore, we focused on sex-dependent regulation of compared with non-metastatic tumors (George et al. ERβ expression in CRC patients and analyzed it with 2001). An association between negative or low respect to clock and VEGF-A expression. expression of VEGF in tumor tissue and better survival was also observed in patients with CRC (Bendardaf et al. Methods 2017). Angiogenesis that accompanies tumor expansion The cohort consisted of 64 patients of both is inhibited by ERβ. In mice with implanted T47D breast genders that underwent surgery for colorectal cancer. cancer cells, an ERβ-mediated decrease in VEGF release Detailed clinicopathological characteristics of patients and a reduction in intratumoral vascularization and tumor and tumors are provided in Table 1. All patients were growth were observed (Hartman et al. 2006). In the colon exposed to standard hospital practice with lights on from estrogen has been shown to reduce the multiplicity and 6:00 a.m. to 9:00 p.m. (The First Surgery Department, volume of dimethylhydrazine-induced polyps and University Hospital, Comenius University, Bratislava). decrease VEGF expression (Yang et al. 2013). These Tumor, proximal (≥10 cm from tumor) and distal (≥2 cm effects are probably mediated via estrogen response from tumor) tissues were dissected during the surgery elements present in the VEFG sequence (Hyder et al. performed in a 2-h time window (10:00-12:00 a.m.). 2000). Sample collection was performed from 2008 to 2014. Another modulation of CRC progression is Follow-up lasted until 3 April 2018. Excised tissues were associated with the functioning of the circadian system examined by a hospital pathologist to determine grading (Yang et al. 2017). The molecular principle of circadian and staging. Tissue samples intended for gene expression oscillator function is based on clock gene expression analysis were frozen in liquid nitrogen and stored at creating a basic feedback loop. In humans a negative -70 °C until mRNA extraction. All patients signed component of the feedback loop is created by period an informed consent, and the experimental protocol was 1-3 (PER) genes and cryptochrome 1-2 (CRY) genes, approved by the Ethics committee. while the positive arm is composed of transcriptional 2019 Sex-Dependent Estrogen Receptor β in Human Colorectal Cancer S299 Table 1. Characteristics of the patient cohort. All patients n=64 % Male 38 59.4 Gender Female 26 40.6 Age Mean ± SEM (years) 69 ± 1.4 Right-side 25 39.1 Tumor location Left-side 39 60.9 Well differentiated 11 17.2 Grading stage Moderately differentiated 49 76.6 Poorly differentiated 4 6.3 I 4 6.3 IIA, IIB 29 45.3 Clinical stage IIIA, IIIB 15 23.4 IVA, IVB 16 25.0 TNM classification T1-T2 4 6.3 Primary tumor invasion T3 48 75.0 T4 12 18.8 N0 35 54.7 Regional lymph node N1 13 20.3 N2 16 25.0 M0 48 75.0 Distant metastasis M1 16 25.0 n – number, T – tumor invasion, N – nodal status, M – distant metastasis, SEM – standard error of the mean. RNA from tumor and proximal and distal CRY2 (NM_001127457.2) healthy tissues (70 mg) was extracted with the use of sense 5'-GGAGGCTGGTGTGGAAGTAG-3', RNAzol according to the manufacturer’s instructions antisense 5'-CGTAGGTCTCGTCGTGGTTC-3'; (MRC, USA). Synthesis of complementary DNA was VEGF-A (NM_001171623.1) performed with the ImProm-II Reverse Transcription sense 5'-AGAAGGAGGAGGGCAGAATC-3', System (Promega, USA) as described earlier (Herichova antisense 5'-CATCAGGGGCACACAGGAT-3'; et al. 2014). To analyze gene expression QuantiTect ERβ (NM_001437.2) SYBR Green PCR Kit with Sybr-green chemistry sense 5'-TGAGGGGAAATGCGTAGAAGG-3', (QIAGEN, Germany) was used. Quantification was done antisense 5'- CGTTCAGCAAGTGAGCCAG-3'; by StepOnePlus™ Real-Time PCR System (Applied U6 (NR_004394.1) Biosystems, USA).
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