BMI-1影响全反式维A酸对皮肤鳞状细胞癌敏感性及其作用机制

BMI-1 Silencing Enhances Sensitivity of Cutaneous Squamous Cell Carcinoma to All-trans Retinoic Acid

目的全反式维A酸(ATRA)具有促进细胞分化和抑制肿瘤增殖的作用,故可应用于皮肤鳞状细胞癌(cSCC)辅助治疗。然而肿瘤治疗抵抗机制复杂,本研究针对干细胞更新因子BMI-1在cSCC中对ATRA作用敏感性的影响,初步探讨沉默BMI-1增强ATRA作用敏感性的机制。方法选择BMI-1基因高表达的A431细胞系,沉默BMI-1基因,检测BMI-1沉默前后ATRA对培养A431细胞增殖的作用;检测沉默BMI对肿瘤细胞耐药蛋白及维A酸受体RARβ表达的影响;小鼠成瘤实验进一步阐明BMI-1抑制cSCC增殖及对ATRA作用敏感性的影响。结果沉默BMI-1能够显著降低A431细胞的增殖能力(P<0.05),并且增加A431细胞对ATRA作用的敏感性(P<0.05);BMI-1沉默能够降低耐药蛋白表达并上调RARβ表达;小鼠成瘤实验中,沉默BMI-1能够显著增强ATRA对cSCC增殖的抑制。结论在cSCC中,沉默BMI-1能够抑制肿瘤细胞增殖、降低耐药蛋白表达及上调维A酸受体RARβ表达,从而增加ATRA对cSCC抑制作用的敏感性。

Objective All-trans retinoic acid(ATRA)inhibits the progress of cutaneous squamous cell carcinoma(cSCC)by regulating differentiation and proliferation and is considered an anti-cancer chemotherapy drug for cSCC.However,clinical drug resistance in the clinic is a frequent problem.This study investigated whether silencing BMI-1 might enhance the sensitivity of cSCC to ATRA.Methods BMI-1 was knocked down in the cSCC A431 cell line.The inhibitory effect of ATRA on A431 cell proliferation was assessed by MTT and EDU.The expression of drug resistance-related proteins and retinoic acid receptorβ(RARβ)was detected by qRT-PCR and western blot.The in vivo effect of BMI-1 on the antitumor activity of ATRA was studied on A431 murine cancer in BALB/c-nude mice.Results Knockdown of BMI-1 significantly inhibited growth and increased sensitivity of A431 cells to ATRA in vitro and in vivo(P<0.05).Furthermore,we proved that decreased levels of ABC transporters(ABCC3 and ABCB1)and increased RARβcontributed to the BMI-mediated effect(P<0.05).Conclusion We propose that elevated levels of BMI-1 contribute to the progression of cSCC,while BMI-1 knockdown can enhance the chemosensitivity of A431 cells to ATRA treatment by inhibiting the proliferation of cancer cells,decreasing the ABC transporters and upregulating RARβ.