Douard Richard, Moutereau Stéphane, Pernet Pascal, Chimingqi Mihelaiti, Allory Yves, Manivet Philippe, Conti Marc, Vaubourdolle Michel, Cugnenc Paul-Henri, Loric Sylvain
General Surgery Department, APHP Georges Pompidou University Hospital, Paris.
Surgery. 2006 May;139(5):665-70. doi: 10.1016/j.surg.2005.10.012.
The Hedgehog (Hh) gene family is known to regulate development of stem cells. In addition, activation is responsible for the induction of GLI1 proto-oncogene and subsequent cellular proliferation. Sonic Hedgehog (SHh), one of the Hh family members promotes carcinogenesis in airway and pancreatic epithelia, is expressed in colonic stem cells. As differentiated colonic cells arise from constant renewal of Hedgehog-expressing colonic stem cells, SHh could be involved in human colonic carcinogenesis.
Tissue samples of colorectal adenocarcinoma (T) and adjacent normal colon tissue (NT) were sampled from each of 44 consecutive patients with colorectal cancer. Specific transcription of SHh, GLI1, and the GLI1 downstream target FOXM1 were evaluated using semiquantitative reverse transcriptase polymerase chain reaction. Similar in vitro measurements of mRNA of GLI1 and FOXM1 transcription levels after specific induction by SHh-Np were performed in the HT-29 colorectal tumor cell line to confirm the in vivo results.
SHh mRNA was overexpressed in colorectal adenocarcinomas in 38 of 44 (86%) patients. Expression of transcription levels of GLI1 and FOXM1 correlated with SHh expression (SHh vs GLI1, r = 0.77, P < .0001; GLI1 vs FOXM1, r = 0.68, P < .0001; SHh vs FOXM1, r = 0.79, P < .0001). SHh overexpression did not appear to correlate with the patient characteristics evaluated. Similarly, when studied in the HT-29 colorectal cell line, exogenous SHh promoted cell proliferation, while inhibition of SHh expression decreased proliferation. Expression of GLI1 and FOXM1 mRNA increased with exogenous exposure to SHh.
We demonstrated increased expression of SHh mRNA in human colonic adenocarcinomas and in a colorectal cell line with downstream increased expression of GLI1 and FOXM1 mRNA known to promote cell proliferation. This upregulation within human colorectal adenocarcinoma tissue confirms the potential role of the Hh pathway in colorectal carcinogenesis and suggests a potential therapeutic target of Hh blockade in colorectal cancer.
已知刺猬（Hh）基因家族可调节干细胞的发育。此外，激活作用会导致GLI1原癌基因的诱导及随后的细胞增殖。声波刺猬因子（SHh）是Hh家族成员之一，可促进气道和胰腺上皮细胞的癌变，在结肠干细胞中表达。由于分化的结肠细胞源自表达刺猬因子的结肠干细胞的持续更新，SHh可能参与人类结肠癌的发生。
从44例连续的结肠癌患者中分别采集结直肠癌组织样本（T）和相邻正常结肠组织样本（NT）。使用半定量逆转录聚合酶链反应评估SHh、GLI1以及GLI1下游靶点FOXM1的特异性转录。在HT-29结直肠肿瘤细胞系中，对经SHh-Np特异性诱导后的GLI1和FOXM1转录水平的mRNA进行类似的体外测量，以证实体内结果。
44例患者中有38例（86%）的结直肠癌组织中SHh mRNA过表达。GLI1和FOXM1的转录水平表达与SHh表达相关（SHh与GLI1，r = 0.77，P <.0001；GLI1与FOXM1，r = 0.68，P <.0001；SHh与FOXM1，r = 0.79，P <.0001）。SHh过表达似乎与所评估的患者特征无关。同样，在HT-29结直肠细胞系中研究时，外源性SHh促进细胞增殖，而抑制SHh表达则降低增殖。随着外源性暴露于SHh，GLI1和FOXM1 mRNA的表达增加。
我们证明了人类结肠腺癌组织及结直肠细胞系中SHh mRNA表达增加，且其下游已知可促进细胞增殖的GLI1和FOXM1 mRNA表达也增加。人类结直肠癌组织中的这种上调证实了Hh信号通路在结直肠癌发生中的潜在作用，并提示了Hh阻断在结直肠癌中的潜在治疗靶点。
