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  • br Introduction br Colon cancer is the third


    1. Introduction
    Colon cancer is the third most common malignancy worldwide, and is associated with a high mortality rate [1]. Since an early diagnosis of colon cancer is rare, the presence of invasive or distant metastases of colon cancer Collagenase Ⅳ into the surrounding tissues and the existing treat-ment methods (e.g., surgical resection and/or chemotherapy) cannot completely inhibit the recurrence and metastasis of colon cancer [2]. Epidemiological investigation has revealed that the occurrence and development of colon cancer is closely related to genetics, diet, living environment, intestinal flora, and other factors [3]. Recently, a large number of studies have shown that the dysregulation of various cell signaling pathways play an important role in the occurrence, develop-ment, and metastasis of colon cancer [4]. Therefore, in-depth studies of the molecular mechanism of colon cancer cell-related signal transduc-tion pathways and the development of therapeutic drugs for key
    molecules have been the primary focus of colon cancer research. Protein kinase B (AKT) is at the core of the phosphatidylinositol-3-
    kinase/protein kinase B/mammalian target of rapamycin (P13K/AKT/ mTOR) signal transduction pathway. A variety of growth factors, in-sulin, cytokines, and other mediators can stimulate AKT activation via the P13K/AKT/mTOR pathway. Subsequently, activated AKT can pro-mote the growth and reproduction of tumor cells, inhibit cell apoptosis, promote cancer cell invasion and metastasis, and promote angiogenesis [5]. Currently, three subtypes of AKT that have been identified (i.e., PKBα [AKT1], PKBβ [AKT2], and PKBγ [AKT3]), which play an im-portant role in tumor occurrence and development. Among these three subtypes, AKT2 is closely associated with cancer cell invasion, metas-tasis, angiogenesis, survival, and drug resistance [6]. Moreover, studies have shown that AKT2 is often overexpressed in colon cancer tissues and cells [7]. Although recent studies on the development of activated AKT and tumors have made significant progress [8], a large number of
    Corresponding author at: Zhejiang Academy of Medical Sciences, Hangzhou 310013, Zhejiang, PR China.
    E-mail address: [email protected] (B. Zheng). 1 Contributed equally
    molecular mechanisms involved in the development of AKT2 in colon cancer remain unknown.
    The most prominent metabolic feature of tumors is efficient aerobic glycolysis, known as the Warburg effect. In addition, tumor aerobic glycolysis activity is closely related to the tumor growth rate and in-vasiveness [9]. Hexokinase (HK) is the first rate-limiting enzyme in the glycolytic pathway and catalyzes the production of glucose-6-phos-phate by glucose, which both produces ATP by oxidative phosphor-ylation or glycolysis, and also participates in the synthesis of important substances (e.g., nucleotides) through the pentose phosphate pathway [10]. HK contains four subtypes (i.e., HK1, HK2, HK3, and HK4), each of which has a particular tissue specificity. Among several subtypes, HK2 was found to be significantly up-regulated in various malignant tumors, including breast cancer, malignant pleural mesothelioma, myeloma, colon cancer, pancreatic cancer, and glioblastoma [11]. Re-cent studies have shown that HK2 in tumor cells not only mediates the Warburg effect, but also inhibits tumor cell apoptosis and regulates autophagy to promote tumor proliferation and metastasis [12]. HK2 deletion inhibits glycolysis and oxidative phosphorylation in human hepatocarcinoma and sensitizes cells to metformin [13]. Furthermore, it has Collagenase Ⅳ been confirmed that blocking the expression of the hk2 gene and using small molecule inhibitors of HK2 can kill various tumor cells [14]. Therefore, HK2 may be a potential target for exploring tumor diagnosis and treatment.
    Several studies have also shown that HK2 may be an important downstream effector of the PI3K/AKT/mTOR signaling pathway and may contribute to the development of cancer [15]. In our previous study, we found AKT2 expression was positively correlated with HK2 expression in primary colon cancer specimens (Spearman's R = 0.711, p < .01). However, how HK2 promotes the development and pro-gression of colon cancer and whether it interacts directly with AKT2 remains poorly understood. In the present study, we aimed to elucidate how AKT2 mediates colon cancer invasion, tumorigenesis, and metas-tasis both in vitro and in vivo, and whether these effects are related to HK2.