Dixit Ruhi, Pandey Manoj, Tripathi Sunil Kumar, Dwivedi Amit Nandan Dhar, Shukla Vijay Kumar
Department of General Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221 005, India.
Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221 005, India.
Cancer Treat Res Commun. 2020;23:100173. doi: 10.1016/j.ctarc.2020.100173. Epub 2020 Apr 21.
This manuscript has reported different mutations of β-catenin gene in gallbladder cancer patients which affect GSK-3β phosphorylation site.
Gallbladder carcinoma (GBC) is a relatively rare and fatal cancer with poor prognosis. The molecular mechanism of gallbladder carcinogenesis is still not clear. Wnt signaling pathway is a highly conserved pathway that regulates proliferation, differentiation, migration, genetic stability, apoptosis, and stem cell renewal. β-catenin plays major role in Wnt signaling and aberrations in β-catenin has found to be involved in several cancers pathogenesis. This study was carried out to document the mutations of β-catenin gene in gallbladder cancer and to evaluate its possible role in gallbladder carcinogenesis.
PCR-SSCP (Single Stranded Conformation Polymorphism) for ctnnb1 was performed in 50 patients each of gallbladder cancer, cholelithiasis and 50 healthy controls. Samples that showed variation in banding pattern were sequenced.
Variation in banding pattern was observed in 9 (18%) samples of GBC, 4 (8%) of cholelithiasis and 2 (4%) of control. Sequencing analysis showed 9 novel mutations of ctnnb1 in exon 3 in 18% of gallbladder cancer (χ = 5.778; p < 0.05). Six point mutations, 1 deletion and 1 insertion mutation were found in 9 cases of gallbladder cancer. All point mutations were mis-sense mutation that affected highly conserved serine or threonine region that is important for GSK-3β phosphorylation.
Findings of the study suggests that high frequency of non synonymous mutations of β-catenin gene (ctnnb1) occurs in patients with gallbladder cancer. As these mutations mainly effect GSK 3β phosphorylation, it may be concluded that this might be an important step in gallbladder carcinogenesis. These β-catenin mutations lead to Wnt pathway activation and appear to have a role in progression from inflammation to cancer in gallbladder.
本手稿报道了胆囊癌患者β-连环蛋白基因的不同突变，这些突变影响糖原合成酶激酶-3β（GSK-3β）的磷酸化位点。
胆囊癌（GBC）是一种相对罕见且致命的癌症，预后较差。胆囊癌发生的分子机制仍不清楚。Wnt信号通路是一条高度保守的通路，可调节细胞增殖、分化、迁移、遗传稳定性、凋亡和干细胞更新。β-连环蛋白在Wnt信号中起主要作用，并且已发现β-连环蛋白的异常与多种癌症的发病机制有关。本研究旨在记录胆囊癌中β-连环蛋白基因的突变，并评估其在胆囊癌发生中的可能作用。
对50例胆囊癌患者、50例胆石症患者及50例健康对照进行β-连环蛋白1（ctnnb1）基因的聚合酶链反应-单链构象多态性（PCR-SSCP）检测。对条带模式出现变化的样本进行测序。
在9例（18%）胆囊癌样本、4例（8%）胆石症样本和2例（4%）对照样本中观察到条带模式变化。测序分析显示，18%的胆囊癌患者中ctnnb1基因外显子3有9个新突变（χ² = 5.778；p < 0.05）。在9例胆囊癌病例中发现6个点突变、1个缺失突变和1个插入突变。所有点突变均为错义突变，影响对GSK-3β磷酸化很重要的高度保守的丝氨酸或苏氨酸区域。
该研究结果表明，胆囊癌患者中β-连环蛋白基因（ctnnb1）的非同义突变频率较高。由于这些突变主要影响GSK 3β磷酸化，可以得出结论，这可能是胆囊癌发生中的一个重要步骤。这些β-连环蛋白突变导致Wnt通路激活，似乎在胆囊从炎症到癌症的进展中起作用。
