PDF(Pubmed)
Abstract：
Esophageal Cancer-Related Gene 2 (ECRG2), also known as Serine Peptidase Inhibitor Kazal type 7 (SPINK7), is a novel tumor suppressor gene from the SPINK family of genes that exhibits anticancer potential. ECRG2 was originally identified during efforts to discover genes involved in esophageal tumorigenesis. ECRG2 was one of those genes whose expression was absent or reduced in primary human esophageal cancers. Additionally, absent or reduced ECRG2 expression was also noted in several other types of human malignancies. ECRG2 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, ECRG2 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. ECRG2 function is important also for the regulation of inflammatory responses and the maintenance of epithelial barrier integrity in the esophagus. More recently, ECRG2 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 ECRG2 gene promoter; the treatment of DNA-damaging agents in cancer cells significantly increased p53 binding to the ECRG2 promoter and triggered a strong ECRG2 promoter induction following DNA damage. Further, the genetic depletion of ECRG2 expression significantly impeded apoptotic cell death induced by DNA damage and wild-type p53 in cancer cells. These findings suggest that the loss of ECRG2 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.
摘要：
食管癌相关基因2(ECRG2),也称为丝氨酸肽酶抑制剂Kazal7型（SPINK7），是来自SPINK基因家族的新型肿瘤抑制基因，具有抗癌潜力。ECRG2最初是在努力发现与食管肿瘤发生有关的基因期间鉴定的。ECRG2是在原发性人类食道癌中表达缺失或降低的基因之一。此外,在几种其他类型的人类恶性肿瘤中也注意到ECRG2表达缺失或降低。在各种原发性人类癌症中鉴定了ECRG2错义突变。据报道,源自癌症的ECRG2突变体(位置30处的缬氨酸至谷氨酸)未能诱导由DNA损伤性抗癌药物触发的细胞死亡和半胱天冬酶激活。此外，ECRG2抑制了培养细胞和动物移植肿瘤中的癌细胞增殖，并抑制了癌细胞的迁移/侵袭和转移。ECRG2也被鉴定为Hu抗原R（HuR）的负调节因子，一种致癌RNA结合蛋白，已知可调节mRNA稳定性和与许多癌症相关基因相对应的转录本的表达。ECRG2功能对于调节食管中的炎症反应和维持上皮屏障完整性也是重要的。最近,ECRG2被发现是p53促凋亡转录靶标的最新成员之一。在ECRG2基因启动子的近端区域内发现了两个p53结合位点（BS-1和BS-2）；癌细胞中DNA损伤剂的处理显着增加了p53与ECRG2启动子的结合，并在DNA损伤后触发了强的ECRG2启动子诱导。Further,ECRG2表达的基因缺失显著阻碍了癌细胞中DNA损伤和野生型p53诱导的凋亡细胞死亡。这些发现表明，ECRG2表达的丧失，通常在人类癌症中观察到，可能在赋予人类癌症抗癌药物抗性方面发挥重要作用。因此，ECRG2是DNA损伤诱导的细胞死亡的新型调节剂，也可能是抗癌治疗的潜在靶标。
