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Esophageal Cancer-Related Gene 2 (<i>ECRG2</i>), also known as Serine Peptidase Inhibitor Kazal type 7 (<i>SPINK7</i>), is a novel tumor suppressor gene from the <i>SPINK</i> family of genes that exhibits anticancer potential. <i>ECRG2</i> was originally identified during efforts to discover genes involved in esophageal tumorigenesis. <i>ECRG2</i> was one of those genes whose expression was absent or reduced in primary human esophageal cancers. Additionally, absent or reduced <i>ECRG2</i> expression was also noted in several other types of human malignancies. <i>ECRG2</i> missense mutations were identified in various primary human cancers. It was reported that a cancer-derived ECRG2 mutant (valine to glutamic acid at position 30) failed to induce cell death and caspase activation triggered by DNA-damaging anticancer drugs. Furthermore, <i>ECRG2</i> suppressed cancer cell proliferation in cultured cells and grafted tumors in animals and inhibited cancer cell migration/invasion and metastasis. ECRG2 also was identified as a negative regulator of Hu-antigen R (HuR), an oncogenic RNA-binding protein that is known to regulate mRNA stability and the expression of transcripts corresponding to many cancer-related genes. <i>ECRG2</i> function is important also for the regulation of inflammatory responses and the maintenance of epithelial barrier integrity in the esophagus. More recently, <i>ECRG2</i> was discovered as one of the newest members of the pro-apoptotic transcriptional targets of p53. Two p53-binding sites (BS-1 and BS-2) were found within the proximal region of the <i>ECRG2</i> gene promoter; the treatment of DNA-damaging agents in cancer cells significantly increased p53 binding to the <i>ECRG2</i> promoter and triggered a strong <i>ECRG2</i> promoter induction following DNA damage. Further, the genetic depletion of <i>ECRG2</i> expression significantly impeded apoptotic cell death induced by DNA damage and wild-type p53 in cancer cells. These findings suggest that the loss of <i>ECRG2</i> expression, commonly observed in human cancers, could play important roles in conferring anticancer drug resistance in human cancers. Thus, ECRG2 is a novel regulator in DNA damage-induced cell death that may also be a potential target for anticancer therapeutics.