Colorectal cancer (CRC) stands as one of the most common malignant tumors in the digestive tract, with the third-highest incidence and the second-highest mortality rate globally [1]. The development of CRC is associated with the interaction of genetic and environmental factors, among which family history, age, obesity, unhealthy lifestyle, or gut microbiota are considered established risks affecting the disease progression [2], [3]. Surgical resection remains the main treatment for early-stage CRC patients, while platinum-based chemotherapy become the standard treatment for locally advanced or metastatic CRC with extensive cancer cell dissemination [4], [5]. However, during the process of chemotherapy, many patients acquire resistance to chemotherapy, urgently requiring the elucidation of the mechanisms underlying chemotherapy resistance and the proposal of some intervention strategies.
Oxaliplatin is a third-generation platinum compound that exerts its anti-tumor effects primarily by antagonizing DNA replication and transcription [6]. The resistance of CRC patients to oxaliplatin is a great barrier to successful chemotherapy, but the mechanisms underlying resistance have not been fully elucidated yet. Mounting evidence suggested that aerobic glycolysis not only provides sufficient nutrients and energy for the rapid proliferation and metastasis of tumor cells but is also linked with chemotherapy resistance [7], [8]. For example, Wang et al. [9] pointed out that the levels of glycolysis and the generation of Adenosine triphosphate (ATP) were strikingly enhanced in oxaliplatin-resistant CRC cells. Furthermore, exosomes derived from these resistant cells delivered circRNA (circ_0005963) to sensitive cells, boosting glycolysis and inducing resistance in CRC cells in response to oxaliplatin through the miR-122/PKM2 axis [9]. Therefore, a deeper interpretation of the molecular regulatory mechanisms behind glycolysis and oxaliplatin resistance in CRC could proffer potential targets for the treatment of oxaliplatin-resistant patients.
KIF26B, a kinesin family member 26B, plays a crucial role in adhesion and polarization of mesenchymal cells and is highly expressed in various cancers, including CRC, serving as a prognostic marker for cancer [10]. KIF26B has been reported to be highly expressed in medulloblastoma, promoting malignant progression by affecting the phosphorylation expression of key proteins in the PI3K/AKT signaling pathway [11]. Upregulation of KIF26B expression in breast cancer cells leads to decreased levels of Wnt, β-catenin, and cell cycle-related proteins, and this regulation is achieved through ELK1 transcriptional activation of KIF26B [12]. While existing studies have shown that KIF26B promotes CRC progression, the specific regulatory mechanisms during progression are still to be further explored.
Long non-coding RNAs (lncRNAs) are RNA molecules that are longer than 200 nucleotides and do not possess protein-coding capabilities [13]. Notably, abnormal expression of lncRNA has been reported in various cancers, and lncRNA dysregulation is implicated in tumor development and chemotherapy resistance [14], [15]. Through differential analysis of RNA data from CRC patients, we identified a notable upregulation of lncRNA-AC105118.1 in CRC. AC105118.1 is localized in the cytoplasm, and there was a dearth of studies on its biological function. Generally, lncRNAs can interact with target miRNAs through microRNA response elements (MREs) to regulate the transcription of downstream target genes [16]. By prediction, we uncovered that miR-378a-3p may be a target miRNA of AC105118.1. miR-378a-3p has been reported in CRC [17], gastric cancer [18], esophageal squamous cell carcinoma [19] and other diseases as a tumor suppressor. However, whether miR-378a-3p affects CRC oxaliplatin resistance and what is its relationship with AC105118.1 are unexplained.
In this research, we investigated a molecular pathway related to oxaliplatin resistance in CRC using bioinformatics analysis and functional rescue experiments. Our results manifested that AC105118.1 acts as a molecular sponge for miR-378a-3p and modulates the KIF26B expression, leading to an increase in glycolysis levels and ultimately potentiating CRC resistance to oxaliplatin. This investigation established the AC105118.1-miR-378a-3p-KIF26B regulatory network in CRC for the first time and proffered promising therapeutic targets for the chemosensitization of CRC.
