Inhibition of Transketolase Improves the Prognosis of Colorectal Cancer.

Linhao Zhang,Jinhang Gao,Yang Xiao,Xin Quan,Zhiyin Huang,Qiuyu Cai,Chengwei Tang,Chong Zhao

doi:10.3389/fmed.2022.837143

Linhao Zhang, Jinhang Gao + Show 6 more

Open Access

https://doi.org/10.3389/fmed.2022.837143

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Abstract

Colorectal cancer (CRC) remains a heavy health burden worldwide. Transketolase (TKT) is a crucial enzyme in the non-oxidative phase of the Pentose Phosphate Pathway (PPP), and is up-regulated in multiple cancer types. However, the role of TKT in the prognosis of CRC remains unclear. We aimed to explore whether TKT expression is altered in CRC, how TKT is associated with the prognosis of CRC, and whether the regulation of TKT might have an impact on CRC. Differentially expressed genes (DEGs) were identified using bioinformatics analysis. TKT expression was examined in the human colon adenocarcinoma tissue microarray and xenografts. Cell viability, proliferation, migration, and apoptosis assays in vitro were applied to evaluate the protumoral effects of TKT on CRC. TKT was found to be a risk factor for the poor prognosis of CRC by bioinformatics analysis among the DEGs. TKT was significantly up-regulated in colon adenocarcinoma tissues compared with normal colon tissues in patients. Moreover, similar results were found in HCT116 and RKO human colon adenocarcinoma xenografts in nude mice. TKT expression was positively associated with advanced TNM stage, positive lymph nodes, and poor 5 or 10-year overall survival of CRC patients. In vitro, inhibition of TKT reduced cell viability, proliferation, and migration, and induced cell apoptosis. In addition, inhibition of TKT decreased the protein levels of NICD and Hes1. In conclusion, high TKT expression was associated with the poor prognosis of CRC patients. The protumoral effects of downregulating TKT may be realized by suppressing the Notch signaling pathway. TKT may be a new prognostic biomarker and therapeutic target for CRC.

Highlights

Colorectal cancer (CRC) ranks second in mortality and third in incidence among all cancer types worldwide [1]
Compared to normal colon tissues, TKT was highly expressed in CRC tissues, and high TKT expression was associated with worse overall survival, which met our expectations (P = 0.023, Figures 1B,C)
MYH11 expression was lower in CRC tissues than in normal colon tissues, whereas high MYH11 expression indicated poor prognosis in CRC patients (P = 0.024, Supplementary Figure 2)

Summary

Introduction

Colorectal cancer (CRC) ranks second in mortality and third in incidence among all cancer types worldwide [1]. Treatment of CRC usually consists of surgical removal of the tumor, chemotherapy and/or targeted therapy [4]. TKT in Colorectal Cancer there is still a lack of effective therapeutic targets due to tumor metastasis, recurrence and drug resistance [5,6,7]. Previous studies have reported that many factors can influence the prognosis of CRC, including RAS mutational status, HER2 amplification, miRNAs and inflammatory markers [5, 8,9,10]. The lack of targeted drugs for RAS mutations, resistance to anti-EGFR therapy, difficulty in detecting miRNAs and lack of further validation experiments for inflammatory markers restrict their clinical use [4, 11]. Few studies have focused on the relationship between TKT and the prognosis of CRC

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