Syntaxin-6, a Reliable Biomarker for Predicting the Prognosis of Patients with Cancer and the Effectiveness of Immunotherapy

Abstract

Syntaxin-6 (STX6), a vesicular transport protein, is a direct target of the tumor suppressor gene P53, supporting cancer growth dependent on P53. However, STX6′s function in the tumor microenvironment has yet to be reported. In this research, we comprehensively explored the role of the oncogene STX6 in pan-cancer by combining data from several databases, including the Cancer Genome Atlas, CPTAC, cBioPortal, and TIMER. Then, we verified the carcinogenic effect of STX6 in hepatocellular carcinoma (HCC) and colorectal cancer (CRC) through a series of experiments in vitro and in vivo. Bioinformatics analysis demonstrated that STX6 is an oncogene for several cancers and is mainly involved in the cell cycle, epithelial–mesenchymal transition, oxidative phosphorylation, and tumor immune modulation, especially for tumor-associated fibroblasts (CAFs) and NKT cells. Additionally, a high level of STX6 could indicate patients’ resistance to immunotherapy. Our own data indicated that the STX6 level was upregulated in HCC and CRC. Knockdown of the STX6 levels could arrest the cell cycle and restrain cell proliferation, migration, and invasion. RNA-seq indicated that STX6 was significantly involved in pathways for cancer, such as the MAPK signal pathway. In a mouse model, knockdown of STX6 inhibited tumor growth and potentiated anti-PD-1 efficacy. In light of the essential roles STX6 plays in carcinogenesis and cancer immunology, it has the potential to be a predictive biomarker and a target for cancer immunotherapy.

Syntaxin6 contributes to hepatocellular carcinoma tumorigenesis via enhancing STAT3 phosphorylation

“…Previously, STX6 has been shown to be upregulated in several types of tumors, including HCC, colorectal cancer, pancreatic ductal adenocarcinoma, and esophageal cancer [14,[16][17][18][19]. Consistent with these studies, we found that STX6 was highly expressed in HCC tissues compared with paracancerous tissues and the protein level of STX6 was also increased in cancerous tissues.…”

“…In papillary renal cell carcinoma, STX6 promotes tumor tissue angiogenesis, cell proliferation, and migration [15,26], possibly by regulating VEGFR2. STX6 is upregulated in HCC and colorectal cancer, and knockdown of STX6 suppresses cell proliferation, migration, invasion, and cell cycle progression of BEL-7404 HCC cells and HCT116 colorectal cancer cells [16]. In HCC, STX6 expression was significantly correlated with tumor size, Edmondson grade, alpha-fetoprotein level and poor prognosis.…”

“…In renal cell carcinoma, high expression of STX6 is associated with decreased survival of patients [15]. A recent study have found that in colorectal cancer, knocking down STX6 blocks the cell cycle and inhibits cell proliferation, migration and invasion [16].However, the specific function and mechanism of STX6 in hepatocellular carcinoma need to be further clarified. Some reports have documented the abnormal overexpression of STX6 in some human tumors such as HCC, colorectal cancer, pancreatic ductal adenocarcinoma, as well as esophageal cancer [14,[16][17][18], and have found that STX6 is involved in the development of these tumors.…”