STIM1 overexpression promotes colorectal cancer progression, cell motility and COX-2 expression.
Tumor metastasis is the major cause of death among cancer patients, with >90% of cancer-related death attributable to the spreading of metastatic cells to secondary organs. Store-operated Ca(2+) entry (SOCE) is the predominant Ca(2+) entry mechanism in most cancer cells, and stromal interaction molecule 1 (STIM1) is the endoplasmic reticulum (ER) Ca(2+) sensor for store-operated channels. Here we reported that the STIM1 was overexpressed in colorectal cancer (CRC) patients. STIM1 overexpression in CRC was significantly associated with tumor size, depth of invasion, lymph node metastasis status and serum levels of carcinoembryonic antigen. Furthermore, ectopic expression of STIM1 promoted CRC cell motility, while depletion of STIM1 with short hairpin RNA inhibited CRC cell migration. Our data further suggested that STIM1 promoted CRC cell migration through increasing the expression of cyclooxygenase-2 (COX-2) and production of prostaglandin E2 (PGE2). Importantly, ectopically expressed COX-2 or exogenous PGE2 were able to rescue migration defect in STIM1 knockdown CRC cells, and inhibition of COX-2 with ibuprofen and indomethacin abrogated STIM1-mediated CRC cell motility. In short, our data provided clinicopathological significance for STIM1 and SOCE in CRC progression, and implicated a role for COX-2 in STIM1-mediated CRC metastasis. Our studies also suggested a new approach to inhibit STIM1-mediated metastasis with COX-2 inhibitors.
1] Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan [2] Division of Gastrointestinal and General Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan [3] Department of Surgery, Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan [4] Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung, Taiwan.
J-Y
JY
Wang
Comprehensive Melanoma Research Center, Department of Tumor Biology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
J
J
Sun
1] Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan [2] Department of Radiation Oncology, Kaohsiung Medical University Hospital, and Department of Radiation Oncology, Faculty of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
M-Y
MY
Huang
Department of Genomic Medicine, Faculty of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Y-S
YS
Wang
1] Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan [2] Department of Radiation Oncology, Kaohsiung Medical University Hospital, and Department of Radiation Oncology, Faculty of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan [3] Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.
M-F
MF
Hou
Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
Y
Y
Sun
Comprehensive Melanoma Research Center, Department of Tumor Biology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
H
H
He
Comprehensive Melanoma Research Center, Department of Tumor Biology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
N
N
Krishna
1] Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan [2] Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan.
S-J
SJ
Chiu
Comprehensive Melanoma Research Center, Department of Tumor Biology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
S
S
Lin
Comprehensive Melanoma Research Center, Department of Tumor Biology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
S
S
Yang
1] Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan [2] Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan [3] Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan [4] Department of Pharmacy, Taipei Medical University-Wanfang Hospital, Taipei, Taiwan.
W-C
WC
Chang
D018938:Caco-2 Cells; D002272:Carcinoembryonic Antigen / Q000097:blood; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000235:genetics*; D015232:Dinoprostone / Q000235:genetics; D018450:Disease Progression; D005260:Female; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008207:Lymphatic Metastasis / Q000235:genetics / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D000071737:Stromal Interaction Molecule 1
D002272:Carcinoembryonic Antigen; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015232:Dinoprostone