Aberrant O-glycosylation contributes to tumorigenesis in human colorectal cancer.

Aberrant O-glycosylation is frequently observed in colorectal cancer (CRC) patients, but it is unclear if it contributes intrinsically to tumorigenesis. Here, we investigated the biological consequences of aberrant O-glycosylation in CRC. We first detected the expression profile of Tn antigen in a serial of human CRC tissues and then explored the genetic and biosynthetic mechanisms. Moreover, we used a human CRC cell line (LS174T), which express Tn antigen, to assess whether aberrant O-glycosylation can directly promote oncogenic properties. It showed that Tn antigen was detected in around 86% human primary and metastatic CRC tissues. Bio-functional investigations showed that T-synthase and Cosmc were both impaired in cancer tissues. A further analysis detected an occurrence of hypermethylation of Cosmc gene, which possibly caused its loss-of-function and a consequent inactive T-synthase. Transfection of LS174T cells with WT Cosmc restored mature O-glycosylation, which subsequently down-regulated cancer cell proliferation, migration and apoptotic-resistant ability. Significantly, the expression of MUC2, a heavily O-glycosylated glycoprotein that plays an essential role in intestinal function, was uniformly reduced in human CRC tissues as well as in LS174T cells. These data suggest that aberrant O-glycosylation contributes to the development of CRC through direct induction of oncogenic properties in cancer cells.

Urinary incontinence as a possible signal of neuromuscular toxicity during immune checkpoint inhibitor treatment: Case report and retrospective pharmacovigilance study.

Background: Immune checkpoint inhibitors (ICIs) are associated with different immune-related adverse events (irAEs), but there is limited evidence regarding the association between urinary incontinence and ICIs. Methods: We described the case of a patient experiencing urinary incontinence who later experienced a series of irAEs such as myocarditis, myositis, and neurologic diseases while on ICI treatment in our hospital. In addition, we queried the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) from the third quarter of 2010 to the third quarter of 2020 to perform a retrospective study to characterize the clinical features of urinary incontinence associated with ICIs. Result: In the FAERS study, 59 cases of ICI-related urinary incontinence were retrieved, and approximately 32.2% of the cases were fatal. Combination therapy with nervous system drugs and age >80 years old were the significant risk factors for fatal outcomes. Among these cases of ICI-related urinary incontinence, 40.7% (n = 24) occurred concomitantly with other adverse events, especially, neurological (fifteen cases), cardiovascular (seven cases), musculoskeletal (six cases), and urological disorders (five cases). Five cases had an overlapping syndrome similar to our case report, including one case of myasthenia gravis with myocarditis and another of myasthenic syndrome with polymyositis. Conclusion: ICI-related urinary incontinence might be a signal of fatal neuromuscular irAEs, especially when it occurs concomitantly with ICI-associated neuromuscular-cardiovascular syndrome. Clinicians should be aware of the occurrence of urinary incontinence to identify potentially lethal irAEs in the early phase.

Correlation of Tn antigen expression with mucins in Chinese patients with colorectal cancer.

Objective: Tn antigen expression, indicative of aberrant O-glycosylation, is frequently observed in human colorectal cancer (CRC) and is proposed to play key roles in tumorigenesis and cancer progression. Tn antigen appears to produce global effects on O-glycosylation of proteins, particularly on mucins. However, the association between expression of Tn antigen and mucins in CRC remains unclear. Here, we investigated the expression profile of Tn antigen as well as MUC1, MUC2, and MUC4 in a series of human CRC tissues, with the aim of determining whether the Tn antigen has an influence on mucins in the development of CRC. Methods: Expression and localization of Tn antigen, MUC1, MUC2, and MUC4 were determined by multiplex immunohistochemical staining in formalin-fixed, paraffin-embedded colonic sections from Chinese patients with primary CRC. Results: The data show that 65 of 78 (83.3%) patients with CRC were found to express Tn antigen, which was most often stained in the apical cell membranes, mucin droplets, and cytoplasm of the cancer tissues. No Tn antigen was detected in normal colonic tissues. Correspondingly, there were altered patterns in the expression of mucins. Compared with normal colonic tissues that were absent of Tn staining, MUC1 and MUC4 showed an up-regulated and diffuse expression pattern in cancer tissues that expressed Tn antigen, whereas MUC2 expression was significantly decreased in Tn-positive cancer tissues. Conclusions: These results indicate that Tn antigen expression is closely associated with altered expression of mucins in human CRC. Tn antigen may promote development of CRC through affecting the associated mucins expression.

Upregulated NNT-AS1, a long noncoding RNA, contributes to proliferation and migration of colorectal cancer cells in vitro and in vivo.

The expression patterns of the long non-coding RNA Nicotinamide Nucleotide Transhydrogenase-antisense RNA1 (NNT-AS1) have not been investigated in the context of cancer. In this study, we aim to investigate the NNT-AS1 expression level in colorectal cancer (CRC) patients and its potential roles in tumor biology. We measured the expression of NNT-AS1 in 70 paired tumor tissues and adjacent normal tissues. NNT-AS1 was expressed higher in tumor tissues than that in adjacent noncancer tissues, and higher expression of NNT-AS1 was significantly correlated with lymph node metastasis (Yes vs. No, P=0.004), TNM stage (I/II vs. III/IV, P=0.004), vessel invasion (Yes vs. No, P=0.002) and differentiation (well and moderate vs. poor, P=0.008). Multivariate analyses revealed that NNT-AS1 expression was an independent predictor of overall survival (P=0.0174) and progression free survival (P=0.0132) for CRC. Knockdown of NNT-AS1 using small interfering RNA (siRNA) significantly impaired CRC cell proliferation, migration and invasion in vitro and silencing NNT-AS1 also suppressed tumor growth and metastasis in nude mice. The western blot experiments revealed that silencing NNT-AS1 inhibited epithelial-mesenchymal transition (EMT) and inactivated MAPK/Erk signaling pathway in CRC cell lines. In conclusion, our studies implied that NNT-AS1 may involve in the development and progression of CRC via its regulation of cell proliferation, migration, and invasion by NNT-AS1-mediated activating of MAPK/Erk signaling pathway and EMT. NNT-AS1 may be a useful diagnostic and prognostic biomarker and a potential therapeutic target in CRC patients.