Distinct Performance of Methylated SEPT9 in Upper and Lower Gastrointestinal Cancers and Combined Detection with Protein Markers.

Background: The performance of methylated SEPT9 (mSEPT9) in lower gastrointestinal (GI) cancer (colorectal cancer) has been extensively investigated; however, its performance in upper GI cancer (esophageal cancer and gastric cancer) and the comparison with lower GI cancer have rarely been studied. Methods: A total of 1854 subjects, including 344 upper GI cancer patients, 459 lower GI cancer patients, and 1051 noncancer subjects, were recruited in this prospective cohort study. A modified single polymerase chain reaction test for detecting mSEPT9 was used for plasma detection. Results: The sensitivity of mSEPT9 for upper and lower GI cancers was 45.3% and 74.8%, and the corresponding specificities were 85.6% and 86.5%, with areas under curve (AUC) of 0.71 and 0.80, respectively. mSEPT9 exhibited lower sensitivity in stage I than stage II-IV cancer, while no difference in sensitivity was observed for different locations in upper or lower GI cancer. No difference in sensitivity was found among gross classifications, pathological classifications, and differentiation in upper GI cancer, but a higher sensitivity in infiltrative cancer and moderate and poorly differentiated cancers was observed in the lower GI. No difference in sensitivity was found between male and female in both cancers, while sensitivity increased with age for both cancers. Cancer antigen 724 (CA724) showed the highest sensitivity for upper GI cancers, and carcinoembryonic antigen (CEA) showed the highest sensitivity for lower GI cancers. The combination of CA724 with mSEPT9 increased the sensitivity to 67.5% in upper GI cancers, and the combination of mSEPT9 with CEA increased the sensitivity to 85.4% in lower GI cancers, with an AUC of 0.90 and 0.95, respectively. Conclusions: mSEPT9 exhibited a higher sensitivity in lower GI cancers than upper GI cancers. The combination of mSEPT9 with protein markers significantly enhanced the detection sensitivity in both cancers.

Overexpression of FOXS1 in gastric cancer cell lines inhibits proliferation, metastasis, and epithelial-mesenchymal transition of tumor through downregulating wnt/ß-catenin pathway.

BACKGROUND: Expression of forkhead box (FOX) superfamily members has been shown to be decreased in cancer, which was linked to poor prognosis of patients. The aim of this study was to investigate the expression of a new FOX superfamily member, FOXS1, in gastric cancer, and the influence of FOXS1 overexpression on the tumorigenesis of gastric cancer cells. The underlying molecular mechanism was also investigated. MATERIALS AND METHODS: FOXS1 expression levels were firstly measured in 15 paired gastric cancer and peritumor tissue using quantitative polymerase chain reaction or immunohistochemistry. Secondly, FOXS1 overexpression models were established in two gastric cancer cell lines (SNU-216 and AGS) and FOXS1 knockdown model was established in SNU-638 gastric cancer cell line. Markers for cell proliferation, metastasis, cell cycle status, and wnt/ß-catenin pathway were evaluated. Influence of FOXS1 overexpression on tumorigenesis was further evaluated in xenograft model. RESULTS: Expression of FOXS1 was significantly decreased in gastric cancer tissue in both messenger RNA and protein levels, compared with peritumor tissue. Our results showed that compared to cell lines transfected with negative control, gastric cancer cell lines with FOXS1 overexpression showed suppressed cell proliferation, metastasis, and increased ratio of G0/G1 phase. Xenograft model also showed suppressed tumor growth in FOXS1 overexpression group. Epithelial-mesenchymal transition was also inhibited when FOXS1 was overexpressed, which was indicated by an increase of E-cadherin expression and decrease in vimentin expression. Further investigation showed that expression of ß-catenin was decreased, together with decreased expression in downstream signaling factors, c-Myc and cyclin-D1 in FOXS1 overexpression cell lines. On the other hand, knockdown of FOXS1 showed opposite trends in the changes of those markers for cell proliferation, metastasis, cell cycle status, and wnt/ß-catenin pathway, compared with FOXS1 overexpression. CONCLUSION: In conclusion, the present study showed that FOXS1 expression is downregulated in most GC cases in our cohort, and this loss of expression may promote cell proliferation and metastasis through upregulation of wnt/ß-catenin pathway.