摘要
目的：结合临床及体内外基础研究探讨转录因子Sox4在宣威女性肺癌中的表达状态、生物学功能及分子作用机制。
方法：
1.宣威女性肺癌患者中转录因子Sox4的表达及临床意义研究：
在通过免疫组织化学方法比较宣威地区女性肺癌(108例)、非宣威地区女性肺癌(94例)及肺良性病变组织(74例,其中宣威地区31例,非宣威地区43例)中Sox4蛋白表达的基础上,分别采集96例宣威女性肺癌患者的癌组织及远端正常肺组织进行液氮速冻及甲醛固定,应用实时荧光定量PCR及免疫组织化学技术检测样本中Sox4基因在mRNA及蛋白水平的表达,结合患者的临床病理特征及预后做Kaplan-Meier单因素生存分析及Cox多因素回归分析。
2.抑制Sox4基因表达对宣威女性肺癌细胞XWLC-05生物学特性的影响及作用
机制研究：利用实时定量PCR方法检测Sox4基因在不同类型肺癌细胞系、正常细胞系及胚胎细胞系中的相对表达水平；在化学合成的Sox4-siRNA有效沉默细胞中Sox4基因表达的基础上,采用基因重组技术构建靶向Sox4基因的shRNA重组质粒表达载体pGFP-V-RS-Sox4shRNA,以脂质体转染宣威女性肺癌细胞XWLC-05;利用透射电镜、MTS法、划痕实验、Transwell实验及流式细胞术检测Sox4基因表达抑制对细胞形态、增殖、迁移、转移及凋亡等生物学功能的影响；同时,采用"Rescue功能回复实验”验证RNA干扰的特异性；使用凋亡核心效应酶caspase-3的抑制剂Ac-DEVD-CHO处理Sox4基因抑制后的XWLC-05细胞,并检测细胞周期、凋亡率、caspase-3总量及活性等凋亡的相关指标,以深入探讨Sox4基因的分子作用机制。
3.抑制Sox4基因表达对宣威女性肺癌裸鼠移植瘤的影响研究：
将稳定转染了靶向Sox4基因干扰质粒pGFP-V-RS-Sox4shRNA的XWLC-05细胞接种于裸小鼠背部皮下,同时以接种稳定转染pGFP-V-RS-scramshRNA的XWLC-05(阴性对照组)细胞、未作任何处理的XWLC-05细胞及生理盐水的裸鼠作为对照,观测裸鼠一般情况、成瘤率、肿瘤生长和转移情况；接种后第25天处死裸鼠,测量离体肿瘤大小和肿瘤重量,计算肿瘤抑制率,并利用免疫组织化学技术检测移植瘤中Sox4、ki-67及caspase-3蛋白的表达。
结果：
1.宣威女性肺癌患者中转录因子Sox4的表达及临床意义研究：
1)Sox4蛋白在女性肺癌组织中的表达显著高于在肺良性病变组织中的表达(P <0.05); Sox4在的宣威女性肺癌组织中的阳性表达率为52.7%,在非宣威女性肺癌组织中的阳性表达率为51.0%,两者间比较差异无统计学意义(P>0.05),表达水平间比较也无明显差异(P>0.05)；但在宣威和非宣威地区女性肺癌的各病理类型间Sox4蛋白的表达存在显著性差异(宣威地区F=24.529,P=0.017；非宣威地区F=26.461,P=0.009),既Sox4蛋白在小细胞肺癌中的表达水平显著低于在非小细胞肺癌中的表达(宣威地区F=7.657,P=0.049；非宣威地区F=9.423,P=0.037)；在非小细胞肺癌中,Sox4蛋白在肺腺癌中的表达水平显著高于在其他类型肺癌中的表达(宣威地区F=18.510,P=0.000：非宣威地区F=19.518,P=0.000)。
2)宣威女性肺癌患者肿瘤组织及远端正常肺组织中Sox4mRNA的表达水平分别为2.53±0.35和1.43±0.18,差异有统计学意义(P=0.003)；免疫组织化学检测显示Sox4蛋白主要表达于细胞核,在肺癌组织中的阳性表达率53.1%(51/96)显著高于在远端正常肺组织中的阳性表达率26.0%(25/96),(P=0.000)；Sox4蛋白在不同临床分期(P=0.000)、淋巴结转移与否(P=0.000)、不同组织学类型(P=0.004)及肿瘤不同分化程度(P=0.002)患者中的表达差异有统计学意义；Kaplan-Meier生存分析显示：Sox4蛋白阳性和阴性表达组的中位生存期分别为26个月和39个月(P=0.000),有淋巴结转移患者的中位生存期短于无淋巴结转移的患者(P=-0.012),进展期患者的中位生存期短于早期患者(P=0.000)；多因素Cox风险回归模型显示：病理分期为宣威女性肺癌预后判断的独立影响因素。
2.抑制Sox4基因表达对宣威女性肺癌细胞XWLC-05生物学特性的影响及作用机制研究：
Sox4基因在各类型肺癌细胞系中的表达水平高于在正常细胞系中的表达(P<0.05),尤其在肺腺癌细胞系中的表达相对较高(P<0.05)；化学合成的Sox4siRNA可有效抑制XWLC-05细胞中Sox4基因的表达并诱导细胞的凋亡(P<0.05),但对细胞的增殖无明显影响(P>0.05)；成功构建了能高效抑制Sox4基因表达的pGFP-V-RS-A-Sox4shRNA重组质粒表达载体；重组质粒转染宣威女性肺癌细胞后,在抑制Sox4基因表达的同时上调了细胞中caspase-3的表达；抑制Sox4基因的表达后细胞出现凋亡形态学改变,细胞的增殖、迁移及转移能力较对照组明显减低,差异有统计学意义(P<0.01); FCM检测显示抑制Sox4基因的表达后细胞出现明显的亚二倍体峰,凋亡率高于对照组细胞(P<0.01)；RNA干扰回复实验(rescue control)排除了RNAi中的脱靶效应,反向验证了Sox4基因表达抑制对宣威女性肺癌细胞生物学功能的影响；caspase-3抑制剂使Sox4基因表达抑制的细胞中caspase-3活性片段明显减少(P<0.01),并显著降低了细胞的凋亡率(P<0.01)。
3.抑制Sox4基因表达对宣威女性肺癌裸鼠移植瘤的影响研究：
除生理盐水组外,接种宣威女性肺癌细胞的裸鼠成瘤率为100%；最早于接种后第6天出现肉眼可见的肿瘤；与对照组相比,抑制Sox4基因表达后裸鼠移植瘤的增长趋势明显受到抑制,离体瘤重及离体肿瘤的体积也显著低于对照组(P<0.01),肿瘤抑制率明显增高(P<0.01)；免疫组织化学染色显示：Sox4、caspase-3和ki-67蛋白均表达于细胞核,其中Sox4和ki-67在实验组细胞中的表达显著低于阴性和空白对照组(P<0.05),而caspase-3的表达组间比较差异无统计学意义(P>0.05)。影像学和病理学检查显示,成瘤小鼠在实验期内均未观察到肿瘤的远处转移。
结论：
1.宣威女性肺癌组织中存在Sox4基因在转录和翻译水平的异常表达升高。
2.转录因子Sox4的表达水平结合临床分期对宣威女性肺癌患者病情评估及预后判断有一定的指导意义。
3.转录因子Sox4可能通过提高细胞的增殖能力及抑制caspase-3依赖的凋亡途径而促进宣威女性肺癌的演变和进展。
Objective:To explore the expression, biological function and molecular mechanism of transcription factor Sox4in Xuanwei female lung cancer by clinical investigation and basic researchs in vitro and in vivo.
Methods:
1. Studies on the expression and clinical significance of transcription factor Sox4in Xuanwei female lung cancer patients:
Comparision of Sox4expression in Xuanwei female lung cancer, non-Xuanwei female lung cancer and benign lung lesions was performed by immunohistochemical staining, after which,96cases of Xuanwei female lung cancer tissue and the corresponding distal normal lung tissue samples were freezed in liquid nitrogen and fixed with formaldehyde separately. Real-time fluorescence quantitative PCR and immunohistochemical techniques were applied to detect their Sox4mRNA and Sox4protein expression, combing with clinical pathological features to perform the Kaplan-Meier univariate survival analysis and multivariate Cox survival analysis.
2. Influence of Sox4gene inhibition on biological characteristics of Xuanwei female lung cancer cell XWLC-05and its mechanism research:
The relative expression level of Sox4gene in different types of lung cancer cell lines, normal cells lines and embryonic cell lines was detected by real-time quantitative PCR. On basis of effectively knocking down of Sox4gene by chemical synthetized siRNA, recombinant plasmid pGFP-V-RS-Sox4shRNA was constructed and transfected into Xuanwei female lung cancer cell line XWLC-05to stably inhibit the expression of Sox4gene. Then cell morphology, proliferation, migration, metastasis abilities and apoptosis were identified by transmission electron microscope, MTS assay, wound-healing assay, transwell assay and flow cytometry. At the same time, by using the " Function rescue experiment" to verify the specificity of RNA interference. In-depth mechanism study of Sox4gene was performed by processing pGFP-V-RS-Sox4shRNA transfected cells with or without caspase-3inhibitor Ac-DEVD-CHO and above apoptosis-correlated items were studied.
3. Studies on the effects of Sox4targeted inhibition on Xuanwei female lung cancer xenografts in nude mice:
XWLC-05cells stably transfected by plasmid pGFP-V-RS-Sox4shRNA were inoculated in the nude mice, taking mice inoculated with cells transfected by plasmid pGFP-V-RS-scramshRNA, without transfected cells and physiological saline as control. General observations of nude mice physiological state, tumor formation rate and tumor growth were performed. Mice were sacrificed at day25after inoculation. The tumor volume, tumor weight and tumor inhibition rate were measured. Immunohistochemical staining was applied to detect the expression of Sox4, Ki-67and caspase-3protein in the xenograft.
Results:
1. Studies on the expression and clinical significance of transcription factor Sox4in Xuanwei female lung cancer patients:
1) The expression of Sox4protein in female lung cancer tissues was significantly higher than the expression in benign lung lesions (P<0.05); There were52.7%and51.0%positive staining of Sox4in Xuanwei and non-Xuanwei female lung cancer tissues, respectively, which had no significant difference between expression level (P>0.05) and between positive expression rate (P>0.05). But there was significant difference of Sox4expression among various lung cancer types in Xuanwei and non-Xuanwei female lung cancer,respectively (Xuanwei F=24.529, P=0.017; non-Xuanwei F=26.461, P=0.009), that is Sox4expression in SCLC was significantly lower than that in NSCLC (Xuanwei F=7.657, P=0.049; non-Xuanwei F=9.423, P=0.037),and the expression of Sox4in female adenocarcinoma was significantly higher than that in other types of NSCLC (Xuanwei F=18.510, P=0.000; non-Xuanwei F=19.518, P=0.000).
2) The Sox4mRNA expression level of Xuanwei lung cancer tissues(2.53±0.35) was significant higher than that of matched normal ones(1.43±0.18),(P=0.003). Immunohistochemical staining showed that Sox4protein mainly expressed in cell nucleus. There were53.1%(51/96)positive expression cases in cancer tissues and only26.0%(25/96) in matched normal tissues (P=0.000); There were significant difference in the expression of Sox4protein among patients with different pathological grade (P=0.000),different histological types (P=0.004),whether or not had lymph node metastasis (P=0.000) and the degree of tumor differentiation (P=0.002). The survival analysis by Kaplan-Meier method showed that the median survival time of Sox4positive-expression and negative-expression patients was26months and39months, respectively (P=0.000).Patients with lymph node metastasis or high pathological grade had significant shorter median survival time than those without lymph node metastasis (P=0.012) or low pathological grade (P=0.000); Cox regression survival analysis showed that pathological grade was a significant independent factor affecting prognosis.
2. Influence of Sox4gene inhibition on biological characteristics of Xuanwei female lung cancer cell XWLC-05and its mechanism research:
Expression of Sox4gene in various types of lung cancer cell lines was higher than the expression in normal cell lines(P<0.05), especially highly expressed in lung adenocarcinoma cell lines(P<0.05). Sox4siRNA synthesised by chemical methods can effectively inhibit the expression of Sox4gene in XWLC-05cells and induce cell apoptosis (P<0.05), but it had no significant effects on the proliferation of cells (P>0.05). Recombinant plasmid pGFP-V-RS-A-Sox4shRNA was successfully constructed and efficiently transfected into XWLC-05cells. The Sox4expression was significantly down-regulated (P<0.01) and the caspase-3expression was significantly up-regulated (P<0.01) after transfection when compared with non-transfected cells. The apoptosis morphological changes were observed by microscope and the cell proliferation, migration and metastasis ability were significantly decreased after inhibiting the Sox4expression (P<0.01). FCM showed there had obvious sub-G1peak and higher apoptosis rate in pGFP-V-RS-A-Sox4shRNA transfected cells when compared with control(P<0.01). Rescue assay ruled out the off-target effects in RNAi and so verified the effects of Sox4gene inhibition on Xuanwei female lung cancer cells. Ac-DEVD-CHO treatment obviously inhibited caspase-3activating (P<0.01) and cell apoptosis (P <0.01) in Sox4gene knock-downed cells when compared with control.
3. Studies on the effects of Sox4targeted inhibition on Xuanwei female lung cancer xenografts in nude mice:
Tumor formation rate was100%in tested mice except the mice inoculated with saline. Visible tumors were observed as early as6days after transplantation. Tumor growth of xenograft was significantly slow down after inhibiting the expression of Sox4gene, while the isolated tumor weight and volume of Sox4-inhibited mice were significantly lower than the control (P<0.01).The tumor inhibition rate of Sox4-silenced mice was higher than the control(P<0.01).Immunohistochemical staining showed:Sox4,caspase-3and ki-67protein all expressed in cells nucleus, among which, the expression of Sox4and ki67were significant decreased in Sox4gene inhibited xenograft when compared with negative control and blank control (P <0.05), the expression of caspase-3had no significant difference in all group of mice (P>0.05). no tumor-bearing mice showed metastasis through imaging and pathological examination.
Conclusions:
1. There was abnormally up-regulated expression of Sox4gene at transcription and translation level in Xuanwei female lung cancer tissues.
2. Sox4expression level combining pathological grade can be used as an assessment and prognosis-estimation reference for Xuanwei female lung cancer patients.
3. Transcription factor Sox4may promote the progression of Xuanwei female lung cancer by enhancing cell proliferation ability and inhibiting the caspase-3dependent apoptosis pathway.
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