C1GALT1, Negatively Regulated by miR-181d-5p, Promotes Tumor Progression via Upregulating RAC1 in Lung Adenocarcinoma

Abstract

Glycosyltransferases are frequently dysregulated in lung cancer. Core 1 β 1, 3-galactosyltransferase 1 (C1GALT1), an enzyme highly expressed in various cancers, is correlated with tumor initiation and development. However, the role of C1GALT1 in lung cancer remains poorly understood. In this study, through bioinformatic analysis and clinical validation, we first discovered that C1GALT1 expression was upregulated in lung adenocarcinoma (LUAD) tissues and was closely related to poor prognosis in patients with LUAD. Gain- and loss-of-function experiments showed that C1GALT1 promoted LUAD cell proliferation, migration, and invasion in vitro, as well as tumor formation in vivo. Further investigation demonstrated that RAC1 expression was positively regulated by C1GALT1 in LUAD, whereas silencing Rac1 could reverse C1GALT1-induced tumor growth and metastasis. Moreover, miR-181d-5p was identified as a negative regulator for C1GALT1 in LUAD. As expected, the inhibitory effects of miR-181d-5p on LUAD cell proliferation, migration, and invasion were counteracted by restoration of C1GALT1. In summary, our results highlight the importance of the miR-181d-5p/C1GALT1/RAC1 regulatory axis during LUAD progression. Thus, C1GALT1 may serve as a potential therapeutic target for LUAD.

Expression and Impact of C1GalT1 in Cancer Development and Progression

“…More lung metastasis was observed in mice injected with higher C1GalT-expressing SW480 cells than those injected with lower C1GalT-expressing SW620 cells [ 24 ]. Similar results were also seen in mice inoculated with gastric, hepatocellular, head and neck, lung, and prostate cancer cells [ 23 , 28 , 30 , 33 , 35 , 38 ]. These studies indicate that overexpression of C1GalT1 in cancer promote cancer development, progression, and metastasis.…”

“…Overexpression of C1GalT1 occurs in various cancer types of epithelial origin. Significantly higher C1GalT1 expression at protein or mRNA levels is seen in lung [ 23 ], colon [ 24 , 25 ], breast [ 26 , 27 ], gastric [ 28 , 29 ], head and neck [ 30 ], pancreatic [ 31 ], esophageal [ 32 ], prostate [ 33 ], ovarian [ 34 ], and hepatocellular cancers [ 35 ] ( Table 1 ). Overexpression of C1GalT1 is also associated with poorer prognosis and low survival in patients of colon [ 24 ], breast [ 26 ], esophageal and laryngeal [ 32 , 36 ], head and neck [ 30 ], lung [ 23 ], and prostate cancers [ 33 ].…”

“…Significantly higher C1GalT1 expression at protein or mRNA levels is seen in lung [ 23 ], colon [ 24 , 25 ], breast [ 26 , 27 ], gastric [ 28 , 29 ], head and neck [ 30 ], pancreatic [ 31 ], esophageal [ 32 ], prostate [ 33 ], ovarian [ 34 ], and hepatocellular cancers [ 35 ] ( Table 1 ). Overexpression of C1GalT1 is also associated with poorer prognosis and low survival in patients of colon [ 24 ], breast [ 26 ], esophageal and laryngeal [ 32 , 36 ], head and neck [ 30 ], lung [ 23 ], and prostate cancers [ 33 ]. The association of high C1GalT1 expression with poorer prognosis in breast cancer patients can be further enhanced by the presence of high levels of the polypeptide N-acetyl-galactosaminyltransferase (GALNT) family members GALNT1 or GALNT8 [ 37 ].…”

“…It has been suggested that microRNA (miRNA) may also regulate C1GalT1 expression [ 23 ]. Fourteen miRNAs were predicted using Algorithms prediction tool, TargetScan, to modulate C1GalT1 expression.…”

“…Fourteen miRNAs were predicted using Algorithms prediction tool, TargetScan, to modulate C1GalT1 expression. Binding of miR-181d-5q to the 3′UTR site of C1GalT1 indeed decreased C1GalT1 expression in lung cancer cells [ 23 ], while binding of miR-152 to the 3′UTR site on C1GalT1 reduced C1GalT1 expression in gastric cancer cells [ 29 ]. Thus, regulation of C1GalT1 overexpression in cancer occurs at least at the transcription level and likely involves multiple regulators.…”