Overexpression of heparan sulfate 6- O-sulfotransferase-2 in colorectal cancer - PubMed (original) (raw)

doi: 10.3892/mco.2013.151. Epub 2013 Jul 23.

Hideharu Kimura 2, Tokuzo Arao 2, Hiroaki Kato 1, Hidetoshi Hayashi 2, Tomoyuki Nagai 2, Kazuko Matsumoto 2, Marco DE Velasco 2, Yoshihiko Fujita 2, Go Yamanouchi 3, Masao Fukushima 3, Yasuhide Yamada 4, Akihiko Ito 5, Kiyotaka Okuno 1, Kazuto Nishio 2

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Overexpression of heparan sulfate 6- _O_-sulfotransferase-2 in colorectal cancer

Shigeru Hatabe et al. Mol Clin Oncol. 2013 Sep.

Abstract

The heparan sulfate sulfotransferase gene family catalyzes the transfer of sulfate groups to heparan sulfate and regulates various growth factor-receptor signaling pathways. However, the involvement of this gene family in cancer biology has not been elucidated. It was demonstrated that the heparan sulfate D-glucosaminyl 6-_O_-sulfotransferase-2 (HS6ST2) gene is overexpressed in colorectal cancer (CRC) and its clinical significance in patients with CRC was investigated. The mRNA levels of HS6ST2 in clinical CRC samples and various cancer cell lines were assessed using a microarray analysis and quantitative RT-PCR, respectively. An immunohistochemical (IHC) analysis of the HS6ST2 protein was performed using 102 surgical specimens of CRC. The correlations between the HS6ST2 expression status and clinicopathological characteristics were then evaluated. HS6ST2 mRNA was significantly overexpressed by 37-fold in CRC samples compared to paired colonic mucosa. High levels of HS6ST2 mRNA expression were also observed in colorectal, esophageal and lung cancer cell lines. The IHC analysis demonstrated that HS6ST2 was expressed in the cytoplasmic region of CRC cells, but not in normal colonic mucosal cells. Positive staining for HS6ST2 was detected in 40 patients (39.2%). There was no significant association between the clinicopathological characteristics and HS6ST2 expression. However, positive staining for HS6ST2 was associated with a poor survival (P=0.074, log-rank test). In conclusion, HS6ST2 was found to be overexpressed in CRC and its expression tended to be a poor prognostic factor, although the correlation was not significant. These findings indicate that HS6ST2 may be a novel cancer-related marker that may provide insight into the glycobiology of CRC.

Keywords: colorectal cancer; heparan sulfate; heparan sulfate 6-O-sulfotransferase-2.

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Figures

Figure 1

Figure 1

mRNA expression levels of heparan sulfate 6-_O_-sulfotransferase 2 (HS6ST2) in 10 paired colorectal cancer (CRC) and non-cancerous colonic mucosal samples and in various cancer cell lines. (A) Signal intensities of HS6ST2 were obtained from a microarray analysis. HS6ST2 was overexpressed in CRC (gray bars) compared to the paired mucosal samples (black bars) in almost all the patients. (B) The mRNA expression levels of HS6ST2 were assessed using quantitative reverse transcription-polymerase chain reaction in a panel of 83 cancer cell lines. Pt, patient number; Rel. mRNA, normalized mRNA expression levels (HS6ST2/GAPD × 106); GC, gastric cancer; EC, esophageal cancer; PaC, pancreatic cancer; BC, breast cancer; HCC, hepatocellular carcinoma; ProC, prostate cancer; LC, lung cancer.

Figure 2

Figure 2

Immunohistochemical (IHC) analysis for heparan sulfate 6-_O_-sulfotransferase-2 (HS6ST2) in (A) normal tissues and (B) representative images of colorectal cancer (CRC) tissues. IHC stainings of the stomach, adrenal gland and kidney are shown, all of which are representative examples of a strong expression. No expression was observed in normal colonic tissues. The results of the normal tissue array are summarized in Table I. Representative IHC staining in colonic tissues of CRC patients is defined as negative, mildly positive and strongly positive, according to the expression level and staining intensity.

Figure 3

Figure 3

Kaplan-Meier curves for overall survival. Patients were divided into two groups according to their heparan sulfate 6-_O_-sulfotransferase-2 (HS6ST2) expression status (dotted line, HS6ST2-positive group; straight line, HS6ST2-negative group). The P-value was calculated using the log-rank test.

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