摘要
目的探索缺氧诱导因子-1α(HIF-1α)在直肠癌组织中的表达情况并研究其与直肠癌微淋巴管密度(MLVD)和淋巴结微转移的关系。以进一步了解HIF-1α、MLVD在直肠癌淋巴转移机制中的作用,期待从分子水平探索中低位直肠癌保肛手术的适应征。
方法选取安徽医科大学第一附属医院2000年-2003年间手术切除并经病理证实的中低位直肠癌标本40例作为实验组,所有病例在术前均未接受化疗或放疗,并有完整的随访资料。另取40例相应癌旁正常组织作为对照组。应用免疫组化方法测定直肠癌组织、癌旁正常组织中HIF-1α、MLVD的表达水平;同时应用CK-20免疫组织化学方法对实验组中已行常规HE染色阴性的淋巴结检测微转移情况。分析上述指标与直肠癌大小、大体类型、组织分化程度、临床分期、及术后复发的关系;及上述指标之间的关系。
结果1,直肠癌组织中HIF-1αIOD平均值为77385.72,正常癌旁组织中HIF-1αIOD平均值为33091.96。直肠癌组织中HIF-1α的表达水平显著高于正常癌旁组织(P<0.01);直肠癌组织中MLVD平均值为7.26(最大值8.8,最小值6),正常癌旁组织中MLVD平均值为0.26,(最大值0.80,最小值0.00),直肠癌组织中的MLVD表达水平显著高于正常癌旁组织(P<0.01)。采用双变量相关与回归分析发现直肠癌组织中HIF-1α、MLVD之间成正相关关系,(Pearson相关系数r=0.781 P=0.000<0.01)。
2,本组资料共31例有阴性淋巴结,其中有10例淋巴结中发现有癌细胞微转移,21例为淋巴结微转移阴性。淋巴结微转移阳性直肠癌组织中HIF-1αIOD平均值为96740.09,微转移阴性直肠癌组织中HIF-1αIOD平均值为70934.27。淋巴结微转移阳性组HIF-1α的表达水平显著高于微转移阴性组,两者差别具有统计学意义(P<0.05);淋巴结微转移阳性直肠癌组织中MLVD平均值为7.97,微转移阴性直肠癌组织中MLVD平均值为7.24,淋巴结微转移阳性组MLVD的表达水平显著高于淋巴结微转移阴性组,两者差别具有统计学意义(P<0.05)。
3,采用方差分析检测直肠癌组织中HIF-1α、MLVD的表达水平与肿瘤的大小、大体类型、临床分期、淋巴结转移、分化程度等临床病理特征的关系,发现HIF-1α的表达与大体类型无明显相关性(P>0.05),而与肿瘤大小、临床分期、淋巴结转移、分化程度等有显著的相关性(P<0.05);MLVD的表达与肿瘤大小、大体类型无明显相关性(P>0.05),而与临床分期、淋巴结转移、分化程度等有显著的相关性(P<0.05)。
4,采用乘积极限法(Kaplan—Meier Method)分析直肠癌组织中HIF-1α、MLVD、淋巴结微转移情况和患者术后生存期限之间的关系。结果显示HIF-1α、MLVD、淋巴结微转移等因素预后明显相关。将HIF-1α、MLVD、淋巴结微转移纳入Cox风险比例模型分析,发现HIF-1α、MLVD、淋巴结微转移是影响直肠癌患者预后的独立因素。
5,采用方差分析和卡方检验分析直肠癌术后复发和HIF-1α、MLVD及淋巴结微转移的关系,结果显示HIF-1α、MLVD高表达及淋巴结微转移阳性病例术后更容易复发。
结论1,HIF-1α,MLVD在直肠癌的发生、发展过程中起着重要作用,推测HIF-1α可能通过VEGF-C—VEGFR3途径或者其他途径对直肠癌的MLVD的形成起着某种促进作用。
2,直肠癌淋巴转移中存在淋巴结微转移情况,且HIF-1α和MLVD在微转移中起着某种重要促进作用。
3,通过病例随访,HIF-1α、MLVD表达较强的病例患者局部复发机会大、预后较差,术后生存时间较短。术前检测HIF-1α、MLVD可能为低位直肠癌保肛提供分子学的依据。
4,直肠癌中HIF-1α,MLVD的高表达是以某种方式促进直肠癌的淋巴结微转移的情况,推测HIF-1α,MLVD可能可以作为直肠癌靶向治疗的分子基础。
Objective: Explore the expression of hypoxia-inducible factor-1α(HIF-1α) in rectal cancer。And research the relations that hypoxia-inducible factor-1α(HIF-1α) has with micro lymphaticvessel density (MLVD) and colorectal cancer, lymph node metastasis。In order to further understand whether the HIF-1α, MLVD the mechanism of lymphatic metastasis in rectal cancer play a role and look forward to exploring the molecular level from the rectal cancer surgery to adapt to sign。
Method: Select the First Affiliated Hospital of Anhui Medical University in 2000 -2003 years between surgery and pathologically confirmed in 40 cases of low rectal cancer specimens as the experimental group, all patients were not receiving chemotherapy or radiotherapy before surgery, and a complete follow-up data。The other 40 cases taking the corresponding adjacent normal tissues as control group。Were measured by immunohistochemical staining tumor tissue and adjacent normal tissue HIF-1α,MLVD expression levels; the same time, application of CK-20 immunohistochemical staining of the experimental group routine HE staining negative lymph node micrometastases situation。Analysis of these indicators and rectal cancer size, gross type, histological type, preoperative distant metastasis, histological grade, depth of invasion, clinical staging, prognosis, surgery and postoperative recurrence anus relations
Result: 1, Rectal tissue HIF-1αpositive rate for the77385.72, normal adjacent tissue HIF-1αpositive rate for the33091.96, rectal tissue HIF-1αexpression in the average water rectal was significantly higher than in normal adjacent tissues (P <0.05); rectal tissue MLVD 7.26, (maximum8.8, minimum6), normal tissue adjacent to MLVD 0.26 ( maximum0.80, minimum0.00), rectal cancer tissues MLVD expression were significantly higher than normal adjacent tissues (P <0.05 ); Lymph node micrometastases-positive rectal cancer, cancer adjacent tissue HIF-1α, MLVD expression level was significantly higher than those with negative lymph node micrometastases in rectal cancer organizations and cancer tissues, the difference is statistically significant (P <0.05)。
2,Using tests to detect colorectal cancer tissue HIF-1α, MLVD expression levels with tumor size, depth of invasion, gross type, histological type, clinical stage, lymph node micro-metastasis, preoperative distant metastasis, differentiation, etc。the relationship between clinicopathological characteristics and found that HIF-1α, MLVD expression and characteristics of no significant correlation (P> 0.05), but with the characteristics of significant correlation (P <0.05)。
3,Using tests to detect lymph node micrometastases in lymph node micrometastasis-positive group and negative group in HIF-1α, MLVD the expression level of statistically significant differences (P <0.05)。
4,Using Cox regression univariate analysis of clinicopathologic factors and cancer of HIF-1α, MLVD level and the relationship between the prognosis and found that characteristics of the above indicators into the Cox regression proportional hazard model analysis, we found HIF-1α, MLVD degree of differentiation, lymph node micrometastasis is an independent factor affecting the prognosis of rectal cancer (P <0.05)。
5,Using analysis of variance and chi-square test analysis of rectal cancer recurrence and HIF-1α, MLVD and lymph node micro-metastasis showed that HIF-1α, MLVD high expression and lymph node micro-metastasis-positive cases more easily after recurrence.
Conclusion : 1, HIF-1αand MLVD play an important role in the development in the incidence of colorectal cancer, suggesting HIF-1αmay be plays a catalytic role by VEGF-C-VEGFR3 channels or other means of pairs of colorectal cancer in the formation of MLVD。
2, There is micrometastasis in lymph node metastasis of colorectal cancer, HIF-1αand MLVD play in some important catalytic role in micrometastasis。
3, Through the patients were followed up, HIF-1α, MLVD expressed a strong chance of cases of local recurrence in patients with poor prognosis, shorter survival time。Preoperative detection of HIF-1α, MLVD rectal cancer may provide the molecular basis。
4,HIF-1α, MLVD high expression in some way is the promotion of lymph node micrometastases in colorectal cancer cases, suggesting HIF-1α, MLVD likely targeted therapy can be used as the molecular basis of cancer。
引文
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