Gastric cancer is a major malignancy of the gastrointestinal tract, accounting for a large proportion of cancer-related deaths globally1. Diagnosis of early-stage gastric cancer and prediction of the prognosis of gastric cancer patients significantly reduce mortality. Currently, extensive investigation has been carried out to identify biomarkers for diagnosis and prognosis, with some achievements2. However, there are still no biomarkers that can be reliably used for early diagnosis and prognosis of gastric cancer. Therefore, there is still a need for further studies to find robust diagnostic and prognostic biomarkers.
The Ras family of small GTPases (Ras GTPases), which include K-Ras, H-Ras, and N-Ras, act as a molecular switch and play a role in the regulation of cell proliferation (i.e., G1 to S cell cycle restriction checkpoints), metabolism, and transformation3, 4. Ras GTPase-activating proteins (Ras GAPs), such as neurofibromin (NF1) or p120GAP, regulate the transition between inactive GDP-bound Ras and active GTP-bound Ras5. Ras gene mutations, which are found in more than 19% of cancers6, lead to the accumulation of GTP-bound Ras and Ras signaling cascades4. Besides, deregulation of wild-type Ras signals in the absence of Ras mutations exists in many tumors3. Two main mechanisms account for the deregulation of wild-type Ras signals3: over-activation of Ras positive regulators or loss of function of negative regulators. Ras-association domain family (RASSF) belongs to the latter one3.
RASSF consists of 10 members7. All these 10 members contain the Ras-related domain, which enables them to combine with Ras, and form scaffolds to reduce the promoting effects of Ras on cell growth and survival3, 8, and link Ras with pathways regulating apoptosis, aging, autophagy, inflammation, and DNA repair9. RASSF1-6 each owns their Ras-related domain at the C-terminal10 and RASSF7-10 at the N-terminal11. RASSF1-6 each also possesses the SARAH protein-protein interaction motif, which is a conserved mediator in the Hippo pathway 12–14.
It has been reported that RASSF expression is often downregulated in cancers, mainly due to promoter hypermethylation7. Hypermethylation of RASSF family genes is widespread in different tumors, including lung cancer 15, thyroid neoplasm 16, multiple myeloma 17, breast cancer 18, bladder cancer19, and RASSF1 promoter hypermethylation is one of the most common methylation events in human cancers 20. Unlike other members of the RASSF family, RASSF8 promoter remains unmethylated in most cancers; however, previous studies have revealed that the transcript factor E4BP4, as a key transcriptional modulator, inhibits RASSF8 expression through histone methyltransferases, G9a and SUV39H1 21, leading to RASSF8 down-regulation in some cancers.
Previous studies have reported the expression patterns of several individual RASSF family proteins and their diagnostic values in different cancers15–18, 20, but there has been no study on RASSF expression in gastric cancer. Therefore, the present study aimed to explore the expression patterns of RASSF members and their prognostic values in gastric cancer, based on online data mining tools and an R package.