Abstract
The progression of colorectal cancer (CRC) has been well studied and understood with the development of molecular and genetic techniques. However, specific marker(s) that could be used to predict lymph node (LN) involvement, which is the most important prognostic factor for CRC, have not been identified so far. Our previous study, in which network analysis of LN(+) and LN(−) CRC gene expression was carried out with data obtained from the Cancer Genome Atlas, led to the identification of AHA1. AHA1 is a co-chaperone activator of the Hsp90 ATPase activity. However, the role of AHA1 expression in cancer cells is still unclear. To investigate how AHA1 expression regulates the cancer cell progression and/or metastasis of human CRC, the expression levels of AHA1 and Hsp90 were examined in 105 CRC tissue samples and compared with those in paired normal tissue. The RNA expression levels of AHA1 and Hsp90aa1, but not Hsp90ab, were significantly higher in cancer tissues than in adjacent paired normal tissues (p = 0.032 and p = 0.0002, respectively). In particular, AHA1, but not Hsp90aa1 and Hsp90ab, was closely associated with the TNM stage, LN stage, and tumor metastasis (p = 0.035, p = 0.012, and p = 0.0003, respectively). Moreover, the expression of AHA1 was not only higher in the CRC cell lines than in the normal colon fibroblast cell line but was also associated with the progression of these CRC cell lines. Overexpression of AHA1 in SW480 cells increased, whereas suppression of AHA1 expression in HCT116 cells reduced cell migration and invasion through the regulation of Snail, E-cadherin, pSRC, and pAKT, which are associated with EMT signaling. Taken together, our study suggests that AHA1 contributes to the metastatic advantage of human CRC.
Highlights
The progression of colorectal cancer (CRC) has been well studied and understood with the development of molecular and genetic techniques
Results obtained from IHC staining of AHA1 in CRC and adjacent normal tissues from 20 CRC patients were consistent with the mRNA expression data, in which AHA1 expression was significantly increased in tumors compared to that in adjacent normal tissues (Fig. 1d)
We focused on how AHA1 expression is associated with CRC cancer cell migration and invasion, which is one of the hallmarks of cancer cell progression
Summary
The progression of colorectal cancer (CRC) has been well studied and understood with the development of molecular and genetic techniques. To investigate how AHA1 expression regulates the cancer cell progression and/or metastasis of human CRC, the expression levels of AHA1 and Hsp[90] were examined in 105 CRC tissue samples and compared with those in paired normal tissue. Sometimes pathological examination, even though its usefulness, can make mistake by under-staging, resulting in lost opportunity for adjuvant chemotherapy, and a higher risk of tumor recurrence in patient[6,7] This makes searching other factor or/and method for prediction or diagnosis of lymph node involvement extremely important for patient care. We explored the possible diagnostic and/or prognostic marker(s) that might help investigate LN involvement in CRC, by comparing the networks of gene expression in LN(+) and LN(−) CRC using datasets from the Cancer Genome Atlas (TCGA) database (https://cancergenome.nih.gov/), and identified significantly different genes in the gene n etworks[8]. We investigated how AHA1 affects cell migration, invasion, and the epithelial mesenchymal transition (EMT) signaling pathway in CRC cells, as well as whether AHA1 expression correlates with clinical pathological characteristics such as TNM stages and MIS, to investigate its potential as a prognostic marker of CRC
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