Cancer Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
Department of Thoracic Surgery, Tumor Hospital, Xinjiang Medical University, Urumqi, China.
Biomed Pharmacother. 2017 Oct;94:813-819. doi: 10.1016/j.biopha.2017.07.154. Epub 2017 Aug 10.
Progestin and adipoQ receptor family member 3 (PAQR3) has exhibited anticancer activity in multiple malignancies. However, its expression and function in esophageal squamous cell carcinoma (ESCC) is still elusive. In this work, we examined the expression of PAQR3 in 40 surgically resected ESCC specimens and their adjacent normal tissues. The expression of PAQR3 in ESCC cell lines was measured after treatment with the demethylating agent 5-aza-2'-deoxycytidine (5-Aza-CdR). The effects of overexpression of PAQR3 on cell proliferation, colony formation, invasion, and tumorigenesis were investigated. It was found that the PAQR3 mRNA level was significantly lower in ESCC than that in adjacent normal tissues (P=0.0318). Low PAQR3 expression was significantly associated with more advanced TNM stage (P=0.0093) and absent lymph node involvement (P=0.0324). Compared to normal esophageal epithelial cells, ESCC cells had significantly lower levels of PAQR3. 5-Aza-CdR treatment led to an induction of PAQR3 in ESCC cells. Enforced expression of PAQR3 significantly inhibited ESCC cell proliferation, colony formation and invasion. Moreover, PAQR3 overexpression blocked cell cycle transition from G1 to S phase, which was associated with induction of p27 and p21 and reduction of cyclin D1, CDK4, and CDK2. Mechanistically, overexpression of PAQR3 suppressed the phosphorylation of ERK1/2 in ESCC cells. In vivo tumorigenic studies confirmed that PAQR3 overexpression retarded the growth of ECA-109 xenograft tumors and inhibited the activation of ERK signaling. Taken together, PAQR3 is epigenetically silenced in ESCC and restoration of PAQR3 suppresses the aggressive phenotype of ESCC cells. Therefore, PAQR3 may represent a potential target for the treatment of ESCC.
孕激素和脂肪素 Q 受体家族成员 3（PAQR3）在多种恶性肿瘤中表现出抗癌活性。然而，其在食管鳞状细胞癌（ESCC）中的表达和功能仍不清楚。在这项工作中，我们检测了 40 例手术切除的 ESCC 标本及其相邻正常组织中 PAQR3 的表达。用去甲基化剂 5-氮杂-2'-脱氧胞苷（5-Aza-CdR）处理 ESCC 细胞系后，测量 PAQR3 的表达。研究了过表达 PAQR3 对细胞增殖、集落形成、侵袭和肿瘤发生的影响。结果发现，ESCC 中 PAQR3 mRNA 水平明显低于相邻正常组织（P=0.0318）。低 PAQR3 表达与更晚期的 TNM 分期（P=0.0093）和无淋巴结受累（P=0.0324）显著相关。与正常食管上皮细胞相比，ESCC 细胞中 PAQR3 的水平明显较低。5-Aza-CdR 处理导致 ESCC 细胞中 PAQR3 的诱导。过表达 PAQR3 显著抑制 ESCC 细胞增殖、集落形成和侵袭。此外，PAQR3 过表达阻断细胞周期从 G1 向 S 期的转变，这与 p27 和 p21 的诱导以及 cyclin D1、CDK4 和 CDK2 的减少有关。在机制上，过表达 PAQR3 抑制 ESCC 细胞中 ERK1/2 的磷酸化。体内肿瘤发生研究证实，过表达 PAQR3 可延缓 ECA-109 异种移植肿瘤的生长并抑制 ERK 信号的激活。总之，PAQR3 在 ESCC 中被表观遗传沉默，恢复 PAQR3 可抑制 ESCC 细胞的侵袭表型。因此，PAQR3 可能成为 ESCC 治疗的潜在靶点。
