Mutation Of Integrin α7 (ITGA7) Gene In Hepatocellular Carcinoma And Its Functional Changes

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world.Half of the world’s HCC patients are in China, therefore HCC is responsible for the second greatest cause of cancer mortality in China. Integrinα7(ITGA7), as an important member of integrin adhesion molecule family, suppresses tumor growth, inhibits cell motility and reduces metastasis.According to recent researches, a variety of missense mutations of ITGA7 gene have been found in prostate cancer, leiomyosarcoma, etc. However, ITGA7 mutations are still rarely reported in HCC. In order to reveal molecular mechanisms of HCC metastasis and high-frequency recurrence, it is necessary that analysing ITGA7 gene mutations, mutation frequency and biological significance of mutations in HCC.In this paper, we screened ITGA7 gene’s coding region and promotor region in 270 cases of HCC samples, which collected from Qidong (Jiangsu Province) and Shanghai.A total of 4 different missense mutations were found in 12 cases of HCC tissue samples, and 3 kinds of mutations were found in the promoter region. Bioinformatics analysis suggested that one of the point mutations in the promoter region might change the NFYA element, while another point mutation may bring about a new element named HLTF. We also screened ITGA7 gene mutations in 9 HCC cell lines, in two (HepG2 and Focus) of which were found a missense mutation and a termination mutation. Meanwhile, mutations of tumor suppressor gene TP53 were blasted in the same group of HCC tissue samples. It is interesting that mutations both in ITGA7 and TP53 genes were found in 3 tissue samples. Predictions run by 3 softwares (SIFT, PolyPen and Pmut) showed that these amino acids change can lead to ITGA7 hydrophobic domains change greatly. In order to clarify whether these ITGA7 gene mutations are related to metastasis of HCC,we constructed two cell lines (H1299, SK-Hepl),which were stable expression of the four ITGA7 mutants (P133S, G610D, A1068V and Q1090*), and did three aspects of functional analysis experiments. The results showed that the four kinds of ITGA7 mutants reduced ability of inhibiting cancer cells’growth, significantly decreased ability of promoting cell adhesion, and greatly reduced ability of inhibiting cell migration.These findings suggested ITGA7 may play an important role in the HCC metastasis and recurrence, which will help to develop new clinical diagnosis strategies in this field.