مقالات پذیرفته شده در نهمین کنگره بین المللی زیست پزشکی
Identification and Bioinformatic Analysis of Hexokinase Related Genes in Colorectal Cancer
Identification and Bioinformatic Analysis of Hexokinase Related Genes in Colorectal Cancer
Dariush Noroozian,1,*Fatemeh Mahsa Karamouzian,2Dr. Mohammad Mahdi Eslami,3Dr. Reza Mirlohi,4
1. Genomics Laboratory, Park of Medical Sciences and Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran 2. Genomics Laboratory, Park of Medical Sciences and Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran 3. Member of the Bioinformatics Research Group, Nasim Research Institute, Tehran, Iran 4. Member of the Bioinformatics Research Group, Nasim Research Institute, Tehran, Iran
Introduction: Colorectal cancer (CRC) is the third most common cancer worldwide, following lung cancer, breast cancer in women, and prostate cancer in men, and poses a significant public health threat due to its aggressive and lethal nature [1–4]. According to GLOBOCAN 2022 data, more than 1.9 million new CRC cases were reported, accounting for 9.6% of all cancer cases. The incidence is higher in men than in women, causing over 900,000 deaths in the same year, representing 9.3% of cancer-related mortality [1]. Projections indicate that by 2040, CRC incidence will increase by 63%, and mortality by 73.4% [5]. In Iran, approximately 12,000 new cases and 7,000 deaths were reported in 2020, with predictions suggesting 18,500 new cases by 2025 [1].
The rising prevalence of CRC in younger individuals (<50 years) is of particular concern [6]. Major risk factors include unhealthy lifestyle habits such as obesity, physical inactivity, alcohol consumption, smoking, high-fat diets, and genetic predisposition [7–9]. Familial syndromes, such as Lynch syndrome and familial adenomatous polyposis (FAP), further increase susceptibility to CRC through inherited mutations in DNA repair genes and tumor suppressors. Clinical symptoms often appear at advanced stages and include bowel obstruction, weight loss, anemia, and metastasis to the liver, lungs, bones, and lymph nodes [4]. Unfortunately, CRC is frequently diagnosed at stage IV, with a five-year survival rate of approximately 14% [10]. Consequently, early screening, risk factor reduction, and multimodal treatment strategies—including surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy—are critical [11]. Increasing public awareness also facilitates early detection, improving treatment outcomes and patient prognosis [12].
Recent studies have highlighted metabolic alterations in cancer cells, particularly the preference for anaerobic glycolysis even in the presence of oxygen, a phenomenon known as the “Warburg effect” [4,13]. This metabolic reprogramming allows cancer cells to generate ATP rapidly and provides essential precursors for nucleotide, amino acid, and lipid biosynthesis required for cell proliferation and tumor growth [14]. The Warburg effect has also been implicated in drug resistance, evasion of apoptosis, immune suppression within the tumor microenvironment, and enhanced metastatic potential [13,15]. Understanding the molecular mechanisms underlying this metabolic shift is essential for identifying novel therapeutic targets in CRC.
Hexokinases (HK1–HK4) are key regulatory enzymes in glycolysis, catalyzing the conversion of glucose to glucose-6-phosphate, which is the first committed and rate-limiting step of the pathway [16]. Among these isoforms, HK2 plays a pivotal role in tumor metabolism. HK2 contains two catalytic domains (N-terminal and C-terminal) and can localize to the outer mitochondrial membrane via binding to the voltage-dependent anion channel (VDAC) [17,18]. This localization ensures direct access to ATP generated by mitochondria, thereby facilitating rapid phosphorylation of glucose and promoting high glycolytic flux in cancer cells [16]. Overexpression of HK2 has been shown to increase glucose uptake, enhance lactate production, and drive rapid tumor proliferation [19–21]. Beyond its enzymatic role, HK2 interacts with non-coding RNAs, such as microRNAs and long non-coding RNAs, and participates in signaling pathways that regulate apoptosis, autophagy, and chemoresistance [2,22,23].
Experimental evidence indicates that inhibition or silencing of HK2 suppresses cancer cell proliferation, enhances sensitivity to chemotherapeutic agents such as oxaliplatin, and induces apoptosis [24–27]. These observations have been reported across multiple cancer types, including pancreatic, breast, liver, ovarian, gliomas, gastric, and colorectal cancers [16,18,19,28]. Specifically in CRC, targeting HK2-mediated glycolysis represents a promising approach for overcoming drug resistance, controlling metastasis, and preventing tumor recurrence [26,27]. Recent advances in small-molecule inhibitors, RNA interference, and CRISPR-based strategies have highlighted the feasibility of selectively modulating HK2 activity in tumor cells while minimizing effects on normal tissues.
Given the central role of HK2 in cancer cell metabolism and its influence on tumor growth, metastasis, and therapeutic resistance, the present study focuses on innovative strategies to target glycolysis via HK2 inhibition. By integrating genomic, transcriptomic, and metabolic data, we aim to identify potential molecular targets that can be exploited for CRC therapy. Such approaches are expected to provide novel avenues for improving patient prognosis and developing more effective, personalized treatment strategies. Understanding the interplay between HK2, non-coding RNAs, and signaling pathways also offers insights into the broader metabolic vulnerabilities of CRC, highlighting the importance of metabolic reprogramming as a hallmark of cancer.
Methods: Relevant genetic and transcriptomic data were extracted from public databases including NCBI, Gene, PubChem, and GEO. Genes were selected based on their involvement in oncogenic pathways, mutation profiles, and experimental evidence. Bioinformatics tools were used to analyze gene expression patterns, chromosomal localization, mutation types, and biological functions.
Results: A total of 68 key genes associated with glycolysis and hexokinase activity were identified in CRC. These genes are implicated in critical biological processes such as cell cycle regulation, metastasis, hypoxia response, and oncogenic signaling pathways. Most displayed significantly increased expression in colorectal tumor samples compared to normal tissue.
Conclusion: This study highlights the pivotal role of the hexokinase enzyme family, particularly hexokinase II (HK2), in the metabolic reprogramming of colorectal cancer cells. The upregulation of HK2 and other hexokinase isoforms enhances aerobic glycolysis (the Warburg effect), enabling cancer cells to meet their energy demands for growth and survival under hypoxic and metabolic stress conditions. Furthermore, genetic alterations and complex epigenetic regulations, especially involving non-coding RNAs, play critical roles in modulating the expression of these enzymes and related pathways.
Given the crucial involvement of HK2 in disease progression and drug resistance, targeting this enzyme and its associated pathways presents a promising strategy for colorectal cancer therapy. Combining metabolic-targeted treatments with conventional chemotherapy may improve therapeutic responses and overcome drug resistance. Ultimately, this study provides a foundation for developing novel therapeutic approaches based on glucose metabolism disruption in colorectal cancer, potentially enhancing patient outcomes and quality of life.