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The four-transmembrane protein MAL2 and tumor protein D52 (TPD52) are highly expressed in colorectal cancer and correlated with poor prognosis

PLoS ONE (2017) 12(5)
DOI: 10.1371/journal.pone.0178515
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Abstract

The four-transmembrane protein MAL2 and tumor protein D52 (TPD52) have been shown to be involved in tumorigenesis of various cancers. However, their roles in colorectal cancer (CRC) remain unclear. In this study, we explored the expressions of MAL2 and TPD52 in tumor specimens resected from 123 CRC patients and the prognostic values of the two proteins in CRC. Immunohistochemical analyses showed that MAL2 (P<0.001) and TPD52 (P<0.001) were significantly highly expressed in primary carcinoma tissues compared with adjacent non-cancerous mucosa tissues. And TPD52 exhibited frequent overexpression in liver metastasis tissues relative to primary carcinoma tissues (P = 0.042), while MAL2 in lymphnode and liver metastasis tissues showed no significant elevation. Real-time quantitative PCR (RT-qPCR) showed the identical results. Correlation analyses by Pearson's chisquare test demonstrated that MAL2 in tumors was positively correlated with tumor status (pathological assessment of regional lymph nodes (pN, P = 0.024)), and clinic stage (P = 0.017). Additionally, the expression of TPD52 was detected under the same condition and was shown to be positively correlated withtumor status (pathological assessment of the primary tumor (pT, P = 0.035), distant metastasis (pM, P = 0.001)) and CRC clinicopathology (P = 0.024). Kaplan-Meier survival curves indicated that positive MAL2 (P<0.001) and TPD52 (P<0.001) expressions were associated with poor overall survival (OS) in CRC patients. Multivariate analysis showed that MAL2 and TPD52 expression was an independent prognostic factor for reduced OS of CRC patients. Moreover, overexpression of TPD52 in CRC SW480 cells showed an increased cell migration (P = 0.023) and invasion (P = 0.012) through inducing occurrence of epithelial-mesenchymal transition (EMT) and activating focal adhesion kinase (FAK)-mediated integrin signalling and PI3K/Akt signalling. Whereas TPD52-depleted cells showed the reverse effect. These data suggested that MAL2 and TPD52 might be potential biomarkers for clinical prognosis and might be a promising therapeutic target for CRC.

Figures

  • Table 1. Expression comparison for MAL2 and TPD52 in tissues of patient with CRC.
  • Fig 1. Immunohistochemical staining for MAL2 and TPD52 in non-cancerous mucosa and primary carcinoma tissues of patients with CRC. (A,B) Expression levels of MAL2 and TPD52 in non-cancerous mucosa and primary carcinoma tissues from patients with CRC were detected by immunohistochemical staining (×100, 100 μm; ×400, 20 μm). MAL2 and TPD52 expression levels were quantified as shown as the right bar charts. **P<0.01 compared with non-cancerous mucosa.
  • Fig 2. Immunohistochemical staining for MAL2 and TPD52 in human CRC tissues. (A,B) Expression levels of MAL2 and TPD52 in primary carcinoma tissuesand liver metastasis tissues from patients with CRC were detected by immunohistochemical staining (×100, 100 μm; ×400, 20 μm). MAL2 and TPD52 expression levels were quantified as shown as the right bar charts. *P<0.05 compared with primary carcinoma; N.S., no significance.
  • Fig 3. mRNA expression of MAL2 and TPD52 in human CRC. RT-qPCR was used to detect the mRNA expression of MAL2 and TPD52 in patient tissues. GAPDH was detected as the internal reference. The bar graph showed the amount of MAL2 and TPD52 protein normalized to the amount of GAPDH. *P<0.05, **P <0.01; N.S., no significance.
  • Table 2. MAL2 and TPD52 staining in tumor cells and associations with clinicopathologic characteristics.
  • Fig 4. Kaplan-Meier survival analysis in patients with CRC. (A) Overall survival curves for patients according to the negative (n = 49) and positive (n = 74) expression levels of MAL2 of immunohistochemical variables in tumor cells. (B) Overall survival curves for patients according to the negative (n = 37) and positive (n = 86) expression levels of TPD25 of immunohistochemical variables in tumor cells. (C) Overall survival curves for patients according to the positive and negative expression of MAL2 and TPD52 of immunohistochemical variables in tumor cells.
  • Table 3. Multivariate cox analyses for OS of 123 patients with CRC.
  • Fig 5. TPD52 regulates migration and invasion in CRC SW480 cells. (A) SW480 cells were transfected with PG307-TPD52 overexpression vector (TPD52) or empty PG307 vector as negative control (Ctrl). Also, SW480 cells were transfected with siRNA for TPD52 (siTPD52) or control siRNA (siCtrl). Western blot analysis was used to detect TPD52 protein expression in cells using TPD52 antibody. GAPDH was detected as internal reference. (B,C) The cellular migration and invasion abilities were evaluated by Transwell assay. (D) Akt (Ser473) phosphorylation was detected by Western blotting using the corresponding antibody and Akt protein was examined. (E,F) TPD52-overexpressed SW480 cells were treated with 2 μM LY294002, the PI3K specific inhibitor, for 24 h, and migration and invasion abilities of TPD52-overexpressed and control cells were evaluated. *P<0.05, **P<0.01 compared with control cells; N.S., no significance.

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APA

Li, J., Li, Y., Liu, H., Liu, Y., & Cui, B. (2017). The four-transmembrane protein MAL2 and tumor protein D52 (TPD52) are highly expressed in colorectal cancer and correlated with poor prognosis. PLoS ONE, 12(5). https://doi.org/10.1371/journal.pone.0178515

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