Research ArticleClinical Studies

Clinical Significance of SEC11A Expression in Patients With Locally Advanced Gastric Cancer

HIDEAKI SUEMATSU, KENTARO SAKAMAKI, NAOHIDE OUE, YUKIHIKO HIROSHIMA, YAYOI KIMURA, SHIZUNE ONUMA, ITARU HASHIMOTO, SHINSUKE NAGASAWA, TORU AOYAMA, TAKANOBU YAMADA, HIROSHI TAMAGAWA, TAKASHI OGATA, YASUSHI RINO, MUNETAKA MASUDA, WATARU YASUI, YOHEI MIYAGI and TAKASHI OSHIMA
Anticancer Research December 2022, 42 (12) 5885-5890; DOI: https://doi.org/10.21873/anticanres.16097

Abstract

Background/Aim: SEC11A gene encodes the SPC18 protein, which has been implicated in tumour progression by inducing the secretion of various growth factors. We investigated the clinical significance of SEC11A expression in gastric cancer (GC) tissues in patients with locally advanced gastric cancer (LAGC) after curative resection. Patients and Methods: We estimated SEC11A expression in cancer tissues from 253 pStage II/III GC patients who underwent curative resection using quantitative polymerase chain reaction (PCR) and investigated the relationship of SEC11A expression with clinicopathological factors and survival. Results: SEC11A expression was significantly related to serosal invasion, lymph node metastasis, lymphatic invasion, and pathological stage. The high-SEC11A expression group had a significantly lower survival rate than the low group (5-year survival 52.3% vs. 75.9%; p<0.005). Furthermore, in multivariate analysis, high-SEC11A expression was an independent factor of poor survival (hazard ratio, 2.010; 95% confidence interval=1.303-3.100; p=0.002). Conclusion: SEC11A expression in cancer tissue may be a useful prognostic marker in patients with LAGC after curative resection.

Key Words:

Gastric cancer (GC) was ranked fifth in terms of incidence and fourth as a cause of death among all cancer types worldwide in 2020 (1). The standard treatment for locally advanced GC (LAGC) is curative resection followed by adjuvant chemotherapy. Despite advances in surgery and chemotherapy, the prognosis of GC is poor (2-6). Recently, genomic profiling has been performed in GC, which would promote personalised therapy. Biomarkers that predict survival and drug sensitivity (7-10) have been reported, and personalised therapy combining biomarkers is also attracting attention.

The SEC11A gene encodes the signal peptidase complex 18 (SPC18) protein, which is one of the subunits of the signal peptidase complex that induces the secretion of various growth factors, including transforming growth factor-α (TGF-α). TGF-α is an epidermal growth factor receptor (EGFR) which is involved in cell proliferation and tumour progression pathways (11, 12). SEC11A and SPC18 have been implicated in the pathophysiology and prognosis of various carcinomas including GC (13-15). Therefore, SPC18 could be a potential biomarker in GC; however, the clinical significance of SEC11A gene expression in GC has not been fully elucidated.

Therefore, in this study, we investigated the clinical significance of SEC11A expression in GC tissues in patients with LAGC.

Patients and Methods

Patients and samples. This study was approved by the ethics committees of Kanagawa Cancer Center and Yokohama City University (approval numbers: epidemiological study-29 and 18-7A-4, respectively). Informed consent was obtained from all participants before recruitment. Among the patients who underwent curative resection for stage II/III gastric cancer at Kanagawa Cancer Center and Yokohama City University between 2002 and 2010, samples were collected from 253 individuals who consented to participate. Each tissue specimen was immediately sealed in an optimum cutting temperature compound (Sakura Fine Tech Co., Ltd., Tokyo, Japan) and stored at −80°C. Tissue sections were prepared from frozen specimens and stained with eosin and haematoxylin for histopathologic evaluation. Tissue sections containing more than 80% cancer cells were used for RNA extraction.

Extraction of RNA and synthesis of complementary DNA (cDNA). Total RNA was extracted using TRIzol Reagent (Gibco, Grand Island, NY, USA) from frozen GC tissue and adjacent normal mucosa specimens. iScript cDNA Synthesis Kit (Bio-Rad, Hercules, CA, USA) was used to synthesise cDNA from total RNA.

Quantitative reverse transcription-polymerase chain reaction (qRT-PCR). qRT-PCR was conducted using iQ SYBR Green Supermix (Bio-Rad). Oligonucleotide primers used for SEC11A were: sense primer 5′-TGAGTAAGAAGCCTGCCTTGC-3′, antisense primer 5′-TTCCACCAATCACAGACCAGTATC-3′. The internal control was β-actin, and the oligonucleotide primers used for β-actin were sense primer 5′-AGTTGCGTTACACCCTTTCTTGAC-3′ and antisense primer 5′-GCTCGCTCCAACCGACTGC-3′. PCR reactions were performed in a total volume of 15 μl consisting of 400 nM of each primer, 200 ng cDNA, 7.5 μl of iQ SYBR Green Supermix containing dCTP, dATP, dTTP, and dGTP at a concentration of 400 μM each, and 50 U/ml iTag DNA polymerase. The program for the reactions was set as follows: 95°C for 3 min, cDNA denaturation at 90°C for 10 s for SEC11A and 15 s for β-actin, annealing at 62°C for 10 s for SEC11A and 60°C for 15 min for β-actin mRNA, and primer extension for SEC11A at 72°C for 20 s and β-actin for 30 s, followed by 10 min hold at 72°C. Denaturation, annealing, and extension were performed for 40 cycles. Melting curves were analysed to distinguish specific from nonspecific products and primer dimers. To quantify the expression level of specific genes in the samples, a standard curve was generated for each run and the three points corresponding to the human control cDNA (Clontech Laboratories, Inc., Mountain View, CA, USA) were measured. The concentration of each sample was calculated from its intersection with the standard curve.

Statistical analyses. Statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). Two-sided p-value <0.05 was regarded as statistically significant. SEC11A expression levels in GC tissue and adjacent normal mucosal tissue were compared using the Wilcoxon test. Associations between SEC11A expression levels and clinicopathological factors were analysed using the χ2 test. The relationship between SEC11A expression levels and overall survival (OS) was assessed by the Kaplan–Meier method and compared by the log-rank test. Univariate and multivariate analyses were conducted using Cox proportional hazards models to determine prognostic risk factors.

Results

Comparison of SEC11A gene expression in GC tissue and adjacent normal mucosa. There was no significant difference between SEC11A expression in GC tissues and that in the adjacent normal gastric mucosa (p=0.060; Figure 1).

Figure 1.
Figure 1.

Comparison of SEC11A expression levels in gastric cancer tissues and normal adjacent gastric mucosa showed no significant difference (p=0.218).

Relationship between SEC11A gene expression levels in GC tissues and clinicopathological features in patients with LAGC. The relationship between SEC11A mRNA expression levels and clinicopathological features is shown in Table I. Patients with LAGC were divided into two groups: high-SEC11A and low-SEC11A expression groups based on the median SEC11A expression. The high-SEC11A group showed significantly higher serosal invasion, lymph node metastasis, lymphatic invasion, and pathologic stage progression than the low-SEC11A expression group.

View this table:
Table I.

Characteristics of patients in the presence and absence of SEC11A expression.

Relationship between SEC11A gene expression and 5-year overall survival rate (5Y-OS) in GC tissues. The 5Y-OS of the high-SEC11A expression group in GC tissues was significantly poorer than that of the low expression group (52.3% vs. 75.9%, respectively; p<0.005; Figure 2).

Figure 2.
Figure 2.

Kaplan–Meier survival curves showed that the 5-year overall-survival rate was 52.3% for patients in the high-SEC11A group and 75.9% for those in the low-SEC11A group (p<0.005).

Univariate and multivariate analysis of GC tissue SEC11A expression levels and clinicopathologic factors for overall survival (OS). Univariate analysis revealed that serosal invasion, lymph node metastasis, lymphatic invasion, and SEC11A expression were significant predictors of OS (Table II). On multivariate analysis, SEC11A mRNA expression was an independent predictor of OS (hazard ratio=2.010, 95% confidence interval=1.303-3.100, p=0.002: Table II).

View this table:
Table II.

Univariate and multivariate Cox proportional hazards analyses of the clinicopathological factors for the overall survival.

Discussion

In this study, we investigated the clinical significance of SEC11A expression in GC tissue of patients with LAGC who underwent curative resection. In the study, high expression of SEC11A in GC tissue was significantly associated with poor 5 years-OS. Furthermore, high SEC11A expression was a predictive factor for poor OS.

Initially, we compared the expression of SEC11A in GC tissue with that of adjacent normal mucosa. It has been reported that SEC11A is highly expressed in cancer tissues compared to adjacent normal tissues in bladder cancer and head and neck squamous cell carcinoma (14, 15). In GC, SEC11A was also reported to be highly expressed in GC tissues compared to normal tissues (13, 16). However, in our results, there was no significant difference between SEC11A expression in GC tissues and that in the adjacent normal gastric mucosa.

Subsequently, we investigated the relationship between SEC11A expression and clinicopathological factors. In previous studies, it was reported that SEC11A expression was significantly associated with tumour (T), nodes (N), and metastases (M) (TNM) stage in head and neck squamous cell carcinoma (15). SPC18 expression level has been implicated in histological classification, tumour depth, lymph node metastases, and TNM stage in GC (17). SPC18 expression has also been reported to be involved in tumour depth and TNM stage in oesophageal cancer (14), venous invasion, histological classification, tumour depth, lymph node metastases, and TNM stage in bladder cancer (18), and lymph node metastases and TNM stage in colorectal cancer (19). In our study, high SEC11A expression in GC tissue was associated with venous invasion, tumour depth, lymph node metastases, and TNM stage.

The mechanisms by which SEC11A affects survival in patients with LAGC who underwent curative resection remains unclear. Previous reports have indicated that SPC18 protein induces the secretion of various growth factors such as TGF-α, which are responsible for cancer progression (13, 18). TGF-α is involved in cell differentiation and proliferation (13, 17). These secreted proteins are synthesised as precursors with signal peptides at the amino terminus end and are cleaved by the signal peptidase complex (SPC) after translocation from the endoplasmic reticulum to the plasma membrane (20, 21). SPC has five distinct subunits among which SPC18 and SPC21 are postulated to have catalytic activity (22, 23). Growth factors such as TGF-α and EGF, whose secretion is induced by SPC18, phosphorylate EGFR and activate downstream signalling involving MEK/ERK and PI3K/Akt pathways (11, 12). This activation plays an important role in tumour cell proliferation, differentiation, angiogenesis, invasion, metastasis, and inhibition of apoptosis, and is involved in the progression of various tumour types (24, 25). Activation of MEK/ERK and PI3K/Akt pathways are associated with cancer progression including micrometastases of cancer cells (26-28), which could be involved in the mechanism by which SEC11A expression affects survival in patients with LAGC who underwent curative resection.

This study has several limitations. Firstly, to determine the clinical utility of the protein as a biomarker, both mRNA expression and protein expression must be examined in the same samples. In our study, we did not examine the protein expression of SPC18. Secondly, there is an issue of heterogeneity of cancer tissue. The samples from which mRNA was extracted were 5 mm2 × 30 μm of frozen tissues, including the deepest portion of the tumour, which might not fully represent the entire tumour.

In conclusion, SEC11A expression in GC tissue may be a useful prognostic marker for patients with LAGC after curative resection. Further research on SEC11A as a biomarker in GC may promote novel research on personalised medicine for the better management of patients with GC.

Acknowledgements

This work was supported by JSPS KAKENHI Grant Number JP20K08997.

Footnotes

  • Authors’ Contributions

    Concept and study design were conducted by HS, YH, YM, and TO. Data collection and literature search were performed by HS, SO, HI, SN, and TO. Data analysis and interpretation were performed by HS, YH, TA, YT, and TO. The manuscript and figures were drafted by HS and TO. Finally, the manuscript was revised and approved by all investigators. Thus, all the Authors actively participated in this study.

  • Conflicts of Interest

    The Authors declare that there are no conflicts of interest regarding this study.

  • Received October 2, 2022.
  • Revision received October 5, 2022.
  • Accepted October 6, 2022.

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Clinical Significance of SEC11A Expression in Patients With Locally Advanced Gastric Cancer
HIDEAKI SUEMATSU, KENTARO SAKAMAKI, NAOHIDE OUE, YUKIHIKO HIROSHIMA, YAYOI KIMURA, SHIZUNE ONUMA, ITARU HASHIMOTO, SHINSUKE NAGASAWA, TORU AOYAMA, TAKANOBU YAMADA, HIROSHI TAMAGAWA, TAKASHI OGATA, YASUSHI RINO, MUNETAKA MASUDA, WATARU YASUI, YOHEI MIYAGI, TAKASHI OSHIMA
Anticancer Research Dec 2022, 42 (12) 5885-5890; DOI: 10.21873/anticanres.16097
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