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SPC18 expression is an independent prognostic indicator of patients with esophageal squamous cell carcinoma

山本悠司広島大学

2020.05.28

概要

Esophageal cancer is the sixth most common malignancy worldwide [1]. The two
predominant forms of esophageal cancer are esophageal squamous cell carcinoma (ESCC)
and adenocarcinoma. Globally, ESCC accounts for more than 90% of esophageal cancer.
Most ESCC is diagnosed at an advanced stage, and even superficial ESCC that appears to
extend no further than the submucosa metastasizes to the lymph nodes in 50% of cases [2].
For localized ESCC, surgery is the primary therapeutic option. However, the prognosis is
unsatisfactory, even in curatively resected patients, and the 5-year survival rate is <50% after
surgery [3]. Several prognostic markers, such as nodal status and tumor stage, are currently
accepted for clinical use, and we also previously identified several ESCC -associated genes
[4–6]. However, these genes cannot completely identify which patients are at low or high risk
for disease recurrence. Therefore, there is an urgent need for new prognostic markers and
therapeutic targets for ESCC.
Transforming growth factor (TGF)-α is a mitogenic polypeptide that has a wide
range of biological activities [7]. TGF-α activates epidermal growth factor receptor (EGFR)
and stimulates multiple signaling pathways involved in cell proliferation, anti-apoptosis, and
other processes [8]. Previously, we have reported that signal peptidase complex 18 (SPC18)
induces TGF-α secretion in human gastric cancer cells [9]. SPC18 protein, which is encoded
by the SEC11A gene, is one of the subunits of the signal peptidase complex. Most secretory
proteins contain amino terminal or internal signal peptides that direct their sorting to the
endoplasmic reticulum (ER) [10]. From the ER, proteins are transported to either the
extracellular space or plasma membrane. The ER signal peptides are then cleaved by the
signal peptidase complex. It has been reported that the signal peptidase complex purified from
canine microsomes has five distinct subunits [11]. ...

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Table 1. Relationship between SPC18 expression and clinicopathological characteristics of

ESCC patients

SPC18 expression

Positive

Negative

P valuea

< 65 years

19(21%)

1.000

≥ 65 years

27(29%)

Male

42(46%)

Female

4(4%)

T1a

3(3%)

T1b/2/3/4

43(47%)

16(17%)

N1/2/3

30(33%)

11(12%)

II/III/VI

35(38%)

Negative

15(16%)

Positive

31(34%)

Negative

29(32%)

Positive

17(18%)

Well, moderately

36(39%)

poorly

10(11%)

Negative

33(36%)

Positiive

13(14%)

Age

Sex

0.135

T classification

0.020

N classification

0.059

Stage

0.028

Lymphatic invasion

0.662

Vascular invasion

0.262

Histological classification

0.342

EGFR expression

Chi-squared test

0.068

Yamamoto Y et al. 17

Table 2. Univariate and multivariate Cox regression analyses of SPC18 expression and

survival of ESCC patients

Characteristic

Univariate analysis

Multivariate analysis

HR (95% CI)

P value

≤ 65 years

1 (Ref.)

0.365

> 65 years

0.65 (0.25-1.67)

HR (95% CI)

P value

1 (Ref.)

0.331

Age

Sex

Female

1 (Ref.)

Male

3.51 (0.72-63.3)

0.138

T classification

1 (Ref.)

T2/3/4

7.44 (2.41-32.54)

0.002

2.07 (0.50-11.42)

N classification

1 (Ref.)

N1/2/3

19.88 (4.05-99.21)

0.001

1 (Ref.)

0.015

9.35 (1.45-190.84)

Lymphatic invasion

Negative

1 (Ref.)

0.009

1 (Ref.)

Positive

5.04 (1.43-32.02)

1.41 (0.25-11.23)

Negative

1 (Ref.)

Positive

4.37 (1.69-12.27)

0.706

Vascular invasion

0.002

Histological classification

Well, moderately

1 (Ref.)

poorly

0.83 (0.28-2.23)

0.733

1.39 (0.42-5.34)

0.592

Yamamoto Y et al. 18

EGFR expression

Negative

Positive

1 (Ref.)

3.01 (1.11-7.67)

1 (Ref.)

0.031

2.65 (0.91-7.36)

0.072

SPC18 expression

Negative

1 (Ref.)

Positive

3.85 (1.43-12.13)

HR: hazard ratio; CI: confidence interval

1 (Ref.)

0.006

3.17 (1.14-10.46)

0.027

Yamamoto Y et al. 19

Figure Legends

Fig. 1. Expression of SPC18 in ESCC. a Immunostaining of SPC18 in ESCC. Original

magnification, ×10. b Immunostaining of SPC18 in ESCC. Original magnification, ×400. c

Immunostaining of EGFR in the same ESCC case shown in panel b. Original magnification,

×400. d Kaplan-Meier plot of ESCC patient survival according to SPC18 expression.

Fig. 2. Effect of SPC18 inhibition on ESCC cell lines. a Western blot analysis of SPC18 in

esophageal cancer cell lines. b Western blot analysis of SPC18 in TE-1 cells transfected with

negative control siRNA or SPC18 siRNAs. c Western blot analysis of SPC18 in TE-5 cells

transfected with negative control siRNA or SPC18 siRNAs. d Effect of SPC18 knockdown on

TE-1 cell proliferation. Cell proliferation was assessed by MTT assays at days 1, 2, and 4

after seeding in 96-well plates. e Effect of SPC18 knockdown on TE-5 cell proliferation. Cell

proliferation was assessed by MTT assays at days 1, 2, and 4 after seeding in 96-well plates.

Fig. 3. Western blot analysis of SPC18, Akt, phosphorylated Akt (pAkt), Erk1/2, and

phosphorylated Erk1/2 (pErk1/2) in lysates of TE-5 cells transfected with the negative control

siRNA or SPC18 siRNAs.

Yamamoto Y et al. 20

Yamamoto Y et al. 21

Yamamoto Y et al. 22

Fig. 3

SPC18

Akt

pAkt

Erk1/2

pErk1/2

β-actin

siRNA-3

siRNA-1

Negative

control

TE-5

...

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SPC18 expression is an independent prognostic indicator of patients with esophageal squamous cell carcinoma

概要

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