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The role of mitochondrial folate enzyme MTHFD1L in esophageal squamous cell carcinoma. OBJECTIVE: The lack of novel therapeutic targets poses the major challenge to prolong survival and improve the quality of life for esophageal squamous cell carcinoma (ESCC). Methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) plays critical roles in folate cycle maintenance. However, little information is available concerning the role of MTHFD1L in cancer cells, and no studies have addressed such issues in esophageal cancer. MATERIALS AND METHOD: Surgical cancer and adjacent normal esophageal tissues were obtained from patients with esophagectomy and esophagogastrostomy for ESCC. Western blot, immunohistochemistry and Quantitative RT-PCR were performed to evaluate protein and RNA expression levels of MTHFD1L. Knockdown of MTHFD1L expression was achieved by using short hairpin RNA. The effects of MTHFD1L silencing on ESCC cell proliferation and apoptosis were assessed by the MTT assay, Celigo assays, Annexin V FACS assay and Caspase-3/7 array in vitro. RESULTS: Twenty-three paired cancer and adjacent normal esophageal tissues from patients with ESCC were included in this study. MTHFD1L protein and RNA expression levels were significantly upregulated in ESCC tissue as compared with normal tissue. High expression of MTHFD1 was also detected in two esophageal cancer cell lines (TE-1 and EC109). Knockdown of MTHFD1L expression inhibited the proliferation of TE-1 cells, and the apoptosis was distinctly increased following shMTHFD1L infection. CONCLUSIONS: Our preliminary study highlighted for the first time that MTHFD1L might be involved in the development of ESCC, which may provide a new potential tumor-specific therapeutic targeting for anti-folate agents.