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. 2017 Jan;108(1):143-150.
doi: 10.1111/cas.13121.

Clinicopathological significance of SPC18 in colorectal cancer: SPC18 participates in tumor progression

Takuya Hattori  1 , Kazuhiro Sentani  1 , Oue Naohide  1 , Naoya Sakamoto  1 , Wataru Yasui  1
Affiliations

Clinicopathological significance of SPC18 in colorectal cancer: SPC18 participates in tumor progression

Takuya Hattori et al. Cancer Sci. 2017 Jan.

Abstract

Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. In order to identify novel prognostic markers or therapeutic targets for CRC, we searched for candidate genes in our comprehensive gene expression libraries, and focused on SEC11A, which encodes the SPC18 protein. SPC18 plays a key role in the endoplasmic reticulum-Golgi secretory pathway and presumably regulates the secretion of various secretory proteins. An immunohistochemical analysis of SPC18 in 137 CRC tissue samples demonstrated that 79 (58%) CRC cases were positive for SPC18. SPC18-positive CRC cases were more advanced in terms of N classification (P = 0.0315) and tumor stage (P = 0.0240) than SPC18-negative CRC cases. Furthermore, the expression of SPC18 was an independent prognostic classifier for CRC patients. The cell growth and invasiveness of SPC18 siRNA-transfected CRC cell lines was less than that of the negative control siRNA-transfected cell lines. The levels of phosphorylated epidermal growth factor receptor, Erk and Akt were lower in SPC18 siRNA-transfected CRC cells than in control cells. The expression of SPC18 was colocalized with β-catenin nuclear localization and MMP7 at the invasive front. An immunohistochemical analysis of human colorectal polyp specimens revealed a sequential increase in the expression of SPC18 through the conventional adenoma-carcinoma pathway, while SPC18 was not expressed or was expressed to a lesser extent in serrated pathway-related tumors. These results suggest that SPC18 is involved in tumor progression, and is an independent prognostic classifier in patients with CRC.

Keywords: Colorectal cancer; SPC18; epidermal growth factor receptor; matrix metalloproteinase 7; β-catenin.

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Figures

Figure 1
Figure 1
The immunohistochemical analysis of signal peptidase complex 18 (SPC18) in colorectal cancer (CRC) tissue specimens. (a) SPC18 immunostaining in the non‐neoplastic colonic mucosa and CRC. SPC18 staining was not observed in the non‐neoplastic colonic mucosa, whereas SPC18 staining was observed in CRC cells (original magnification ×40). (b) SPC18 immunostaining in CRC (original magnification ×400). SPC18 staining was observed in CRC cells in the cell cytoplasm. (c) SPC18 immunostaining in CRC (original magnification ×20). SPC18 staining was observed to be stronger in the deeper invasive region of the tumors of CRC. (d) Kaplan–Meier plot of the survival of CRC patients.
Figure 2
Figure 2
The effects of the inhibition of signal peptidase complex 18 (SPC18) on cell growth and invasive activity in colorectal cancer (CRC) cells. (a) The Western blotting of SPC18 in the cell lysates from six CRC cell lines. (b) The Western blotting of SPC18 in cell lysates from DLD‐1 and LoVo transfected with SPC18 siRNA or negative control siRNA. β‐Actin was included as a loading control. (c, d) The effect of SPC18 knockdown on the cell growth of DLD‐1 (c) and LoVo (d). Cell growth was assessed by an MTT assay at 1, 2 and 4 days after seeding on 96‐well plates. The mean (bars) and standard deviation (SD; error bars) of three independent experiments are shown. (e, f) The effect of the knockdown of SPC18 on cell invasion in DLD‐1 (e) and LoVo (f) transfected with SPC18 siRNA (siRNA1 and 3) or negative control siRNA that were incubated in Boyden chambers. After 1 and 2 days, the invading cells were counted. NS, not significant.
Figure 3
Figure 3
The effect of the downregulation of signal peptidase complex 18 (SPC18) on the epidermal growth factor receptor (EGFR) signaling pathway. (a, b) Western blotting of SPC18, EGFR, phospho‐EGFR (pEGFR), Erk1/2, phospho‐Erk1/2 (pErk1/2), Akt, and phospho‐Akt (pAkt) in cell lysates from DLD‐1 (a) and LoVo (b) transfected with SEC11A siRNA or negative control siRNA. β‐Actin was included as a loading control.
Figure 4
Figure 4
The analysis of the correlation between the expression of signal peptidase complex 18 (SPC18) and colorectal cancer (CRC)‐related molecules in the invasive front. (a) The expression levels of SPC18 (b–d) CRC‐related molecules, including β‐catenin, Matrix metalloproteinase 7 (MMP7) and p53, were examined. A serial section showed that the MMP7 and β‐catenin nuclear localization at the invasive front was partially adjacent to the area in which SPC18 was expressed.
Figure 5
Figure 5
The analysis of the expression of signal peptidase complex 18 (SPC18) in pre‐cancerous lesions of each colorectal carcinogenesis pathway. (a–f) The immunostaining of SPC18 in colorectal polyps (CRPs). (a) Conventional adenoma low‐grade: tubular adenoma component, n = 17; (b) Conventional adenoma low‐grade: villous component, n = 7 (c) conventional adenoma high‐grade (CAHG), n = 29; (d) hyperplastic polyp. n = 20; (e) traditional serrated adenoma (TSA), n = 31; and (f) sessile serrated adenoma/polyp (SSA/P), n = 18. (g) The SPC18 immunostaining scores in CRPs. The graph indicates the percentage of sections with different scores (negative, weak, moderate and strong). (h) A representative image of the expression of SPC18 in MSI‐H serrated pathway‐related CRC. NS, not significant.
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