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. 2016 Dec;12(6):5136-5144.
doi: 10.3892/ol.2016.5341. Epub 2016 Nov 2.

Overexpression of Thy1 and ITGA6 is associated with invasion, metastasis and poor prognosis in human gallbladder carcinoma

Dan-Hua Zhang  1 , Zhu-Lin Yang  1 , En-Xiang Zhou  1 , Xiong-Ying Miao  1 , Qiong Zou  2 , Jing-He Li  3 , Lu-Feng Liang  4 , Gui-Xiang Zeng  5 , Sen-Lin Chen  6
Affiliations

Overexpression of Thy1 and ITGA6 is associated with invasion, metastasis and poor prognosis in human gallbladder carcinoma

Dan-Hua Zhang et al. Oncol Lett. 2016 Dec.

Abstract

Gallbladder cancer (GBC) is a rare but highly aggressive cancer for which no well-accepted prognostic biomarkers have been identified. Thymus cell antigen 1 (Thy1), also known as cluster of differentiation (CD)90, and integrin α6 (ITGA6), also known as CD49f, are important molecules in cancer and putative markers of various stem cell types. However, their role in GBC remains to be elucidated. In the present study, Thy1 and ITGA6 expression status in clinical GBC samples, which comprised squamous cell/adenosquamous carcinoma (SC/ASC) and adenocarcinoma (AC) subtypes, was investigated. The associations between Thy1 and ITGA6 expression and clinical parameters and survival rate were analyzed separately. The THY1 and ITGA6 messenger RNA levels were significantly higher in both SC/ASC and AC tissues than in adjacent non-tumor tissues (all P<0.001). These results were subsequently confirmed by immunohistochemical analyses. Overexpression of Thy1 and ITGA6 was correlated with poor differentiation, large tumor size, lymph node metastasis and great invasiveness in SC/ASC (Thy1, P=0.045, P=0.005, P=0.003 and P=0.009, respectively, and ITGA6, P=0.029, P=0.011, P=0.009 and P=0.004, respectively) and AC (Thy1, P=0.027, P<0.001, P=0.003 and P 0.004, respectively, and ITGA6, P=0.002, P=0.003, P=0.006 and P=0.006, respectively). Both Thy1 and ITGA6 were expressed at higher levels in AC with advanced tumor-node-metastasis stage (TNM) than in AC with low TNM stage (P=0.001 and P=0.018, respectively). In addition, patients with elevated Thy1 or ITGA6 expression had shorter overall survival than those with negative Thy1 or ITGA6 expression. Multivariate Cox regression analysis demonstrated that Thy1 (SC/ASC, P=0.001 and AC, P=0.005) and ITGA6 (both P=0.003) were independent predictors of poor prognosis in both SC/ASC and AC patients. In conclusion, Thy1 and ITGA6 could be clinical prognostic markers for GBC.

Keywords: ITGA6; Thy1; gallbladder carcinoma; prognostic markers.

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Figures

Figure 1.
Figure 1.
Thy1 and ITGA6 mRNA levels in clinical tissue samples. (A) The relative levels of Thy1 mRNA in SC/ASC and AC were analyzed by RT-qPCR. Data shown are the mean ± SEM from experiments repeated in triplicate with three samples per treatment. **P<0.001 vs. non-tumor tissues. (B) The relative levels of ITGA6 mRNA transcripts in SC/ASC and AC were analyzed by RT-qPCR. Data shown are the mean ± SEM from experiments repeated in triplicate with three samples per treatment. **P<0.001 vs. non-tumor tissues. SC/ASC, squamous cell/adenosquamous carcinoma; AC, adenocarcinoma; Thy1, thymus cell antigen 1; ITGA6, integrin α6; SEM, standard error of the mean; mRNA, messenger RNA; RT-qPCR, reverse transcription-quantitative polymerase chain reaction.
Figure 2.
Figure 2.
Immunohistochemistry of Thy1 in SC/ASC and AC (magnification, ×200). The expression of Thy1 was localized mainly in the cytoplasm. (A) Positive Thy1 expression in poorly differentiated SC/ASC. (B) Negative Thy1 expression in moderately differentiated SC/ASC. (C) Positive Thy1 expression in well differentiated AC. (D) Negative Thy1 expression in well differentiated AC. SC/ASC, squamous cell/adenosquamous carcinoma; AC, adenocarcinoma; Thy1, thymus cell antigen 1.
Figure 3.
Figure 3.
Immunohistochemistry of ITGA6 in SC/ASC and AC (magnification, ×200). The expression of ITGA6 was localized mainly in the cytoplasm. (A) Positive ITGA6 expression in poorly differentiated SC/ASC. (B) Negative ITGA6 expression in moderately differentiated SC/ASC. (C) Positive ITGA6 expression in moderately differentiated AC. (D) Negative ITGA6 expression in moderately differentiated AC. SC/ASC, squamous cell/adenosquamous carcinoma; AC, adenocarcinoma; ITGA6, integrin α6.
Figure 4.
Figure 4.
Thy1 and ITGA6 expression and survival in patients with SC/ASC. (A) Kaplan-Meier plots of overall survival in patients with SC/ASC and with Thy1-positive and Thy1-negative expression. (B) Kaplan-Meier plots of overall survival in patients with SC/ASC and with ITGA6-positive and ITGA6-negative expression. SC/ASC, squamous cell/adenosquamous carcinoma; ITGA6, integrin α6; Thy1, thymus cell antigen 1.
Figure 5.
Figure 5.
Thy1 and ITGA6 expression and survival in patients with AC. (A) Kaplan-Meier plots of overall survival in patients with AC and with Thy1-positive and Thy1-negative expression. (B) Kaplan-Meier plots of overall survival in patients with AC and with ITGA6-positive and ITGA6-negative expression. AC, adenocarcinoma; ITGA6, integrin α6; Thy1, thymus cell antigen 1.
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