135P - Revealing the third kind of pathway of colorectal cancer developing from laterally spreading tumors

Background

Two classical models have been proposed for the development of colorectal cancer (CRC) from colon epithelial cells, transformation of adenoma and serrated polyps to cancer. However, clinical data showed that there is still a certain amount of CRC is not derived from the above two pathways, forming the theoretical island of CRC pathogenesis. Laterally spreading tumor (LST) is an important precancerous lesion of CRC, while the molecular mechanism of it's carcinogenesis remained unclear.

Methods

We proposed a two-stage cascade mutation hypothesis for LST cancerization. Based on the mRNA data of 25711 samples from 980 healthy donors in the genotype-tissue expression, pan-cancer mRNA-sequencing and survival data.We performed a differential expression and survival analysis of ATM, ANO5, APC, and TP53 in pan-cancer and adjacent normal samples. Furthermore, we validated the noneffective role of PIK3CA signaling pathway in two cell lines, LS174T and SW1116 by constructing three SiRNA (PIK3CA-SiRNA-1, PIK3CA-SiRNA-2, PIK3CA-SiRNA-3), to confirm the vital role of TGFβ and p53 signaling pathway involving in LST cancerization.

Results

The expression profiles of ATM, ANO5, APC and TP53 in normal and pan-cancer samples were significantly downregulated in rectal adenocarcinoma, colon adenocarcinoma, and their joint samples. In contrast, TP53 showed an obviously higher level in all of above samples. ATM, ANO5, APC, and TP53 expression were correlated with the overall survival of colorectal cancer patients. ATM and ANO5, which closely related to the Golgi apparatus fragmentation in LST samples presented a significant changes. The SiRNA interference test showed that the expression level of PIK3CA was not significantly different from the control group.

Conclusions

These findings suggested that early APC mutations induced a Golgi fragmentation event, weakened the expression of wild-type TP53 transcription factor MDM2 and TP73, modulated the stability of mutant TP53, ultimately promoted the carcinogenesis process of the LST. The PI3K signaling pathway is not closely associated with LST carcinogenesis. These observations suggest the existence of a unique and novel pathway for the development of CRC from LST.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

National Natural Science Foundation of China; Gansu Medical College.

Disclosure

The authors have declared no conflicts of interest.