Abstract
BackgroundS100A11 is a member of the S100 family of proteins containing two EF-hand calcium-binding motifs. The dysregulated expression of the S100A11 gene has been implicated in tumour metastasis. However, the role of S100A11 protein in tumour cell response to chemotherapeutic drugs has not been characterised.MethodsTranscript levels of S100A11 in gastric cancer were evaluated using an in-house patient cohort. Protein expression of S100A11 in gastric cancer was estimated by immunohistochemistry of a tissue microarray. The stable gastric cancer cell lines were established using lentiviral shRNA vectors. The knockdown of S100A11 was validated by qRT-PCR, PCR, and Western blot. The cellular function of S100A11 was estimated by assays of cell adhesion, migration, and invasion. The cell cytotoxic assay was performed to investigate the response to chemotherapeutic drugs. An unsupervised hierarchical clustering and principal component analysis (HCPC) was applied to unveil the dimensional role of S100A11 among all S100 family members in gastric cancer.ResultsHigh expression of S100A11 is associated with poor survival of gastric cancer patients (p < 0.001, HR = 1.85) and is an independent prognostic factor of gastric cancer. We demonstrate that S100A11 plays its role as a tumour promoter through regulating the MMP activity and the epithelial-mesenchymal transition (EMT) process. The stable knockdown of S100A11 suppresses the metastatic properties of gastric cancer cells, which include enhancing cell adhesion, but decelerating cell migration and invasion. Furthermore, the knockdown of S100A11 gene expression dramatically induces the cellular response of gastric cancer cells to the first-line chemotherapeutic drugs fluoropyrimidine 5-fluorouracil (5-FU) and cisplatin.ConclusionThe present study identifies S100A11 as a tumour promoter in gastric cancer. More importantly, the S100A11-specific targeting potentially presents dual therapeutic benefits by not only controlling tumour progression but also sensitising chemotherapeutic cytotoxic response.
Highlights
S100A11 is a member of the S100 family of proteins containing two EF-hand calcium-binding motifs
We show for the first time that knockdown of S100A11 in Gastric cancer (GC) cell lines results in the strong induction of apoptosis upon treatment with cisplatin or 5-fluorouracil, suggesting that S100A11 represents promising therapeutic targets to combat GC, or performs as a potential molecular marker to predict the effectiveness of chemotherapy of GC
In summary, we reveal the role of S100A11 in GC and the relationship between S100A11 and chemotherapy resistance in human tumours
Summary
S100A11 is a member of the S100 family of proteins containing two EF-hand calcium-binding motifs. The role of S100A11 protein in tumour cell response to chemotherapeutic drugs has not been characterised. Because most patients lack specific symptoms in the early stage of GC, they are dominantly diagnosed with an advanced tumour that presents with metastasis, often missing the optimal operation time and possessing poor prognosis outcome. Palliative systemic therapy is the optimal choice for advanced gastric tumours, but the initial response. Most of the chemotherapy regimens usually induce DNA damage and trigger apoptosis leading to cell death [6]. Tumour cells could increase DNA repair ability and deregulate apoptosis signaling pathways to resist the therapy response induced by the drugs. Some molecules have been described to coordinate with drugs and positively regulate cell apoptosis upon chemotherapy, which may affect tumour resistance and improve the therapeutic efficiency to combat cancer
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