International Journal of Molecular Medical Science, 2024, Vol.14, No.5, 305-314 http://medscipublisher.com/index.php/ijmms 306 2KRASGene and Its Role in Cancer 2.1 Structure and function of the KRASgene The KRAS gene is a member of the RAS gene family, which also includes HRAS and NRAS. These genes encode small GTPase proteins that act as molecular switches, cycling between an active GTP-bound state and an inactive GDP-bound state. The KRAS protein plays a crucial role in regulating cell proliferation, differentiation, and survival by transmitting signals from cell surface receptors to intracellular signaling pathways such as the MAPK and PI3K pathways (Buscail et al., 2020). The structure of KRAS includes a G-domain responsible for GTP/GDP binding and intrinsic GTPase activity, and a hypervariable region that undergoes post-translational modifications essential for membrane localization and function (Hunter et al., 2015). 2.2 Mechanisms of KRASactivation in cancer KRAS activation in cancer typically occurs through point mutations that result in the protein being constitutively active, meaning it is always in the GTP-bound state and continuously signals downstream pathways regardless of external stimuli. The most common mutations occur at codons 12, 13, and 61, which impair the GTPase activity of KRAS, preventing the hydrolysis of GTP to GDP and thus locking KRAS in its active form. This persistent activation leads to uncontrolled cell proliferation, survival, and metastasis. Additionally, KRAS mutations can cooperate with other genetic alterations, such as TP53 mutations, to enhance tumorigenic processes (Kim et al., 2021). 2.3CommonKRASmutations in pancreatic cancer Pancreatic ductal adenocarcinoma (PDAC) is characterized by a near-universal presence of KRAS mutations, with over 90% of cases exhibiting these alterations (Waters and Der, 2018). The most prevalent mutation in PDAC is KRASG12D, followed by KRASG12V and KRASG12R. These mutations lead to the constitutive activation of KRAS, driving the initiation and maintenance of pancreatic tumors (Luo, 2021). The specific biochemical properties of these mutations, such as altered nucleotide exchange kinetics and interactions with downstream effectors like RAF kinase, contribute to the aggressive nature of PDAC. Furthermore, the presence of KRAS mutations is associated with poor prognosis and resistance to conventional therapies, highlighting the need for targeted therapeutic strategies (Bournet et al., 2016; Tímár and Kashofer, 2020). 3 Genomic Mechanisms of KRASMutations in Pancreatic Cancer 3.1 Molecular pathways affected by KRASmutations KRAS mutations, particularly the KRASG12Dvariant, play a pivotal role in pancreatic cancer by activating several molecular pathways that drive tumorigenesis. Oncogenic KRAS upregulates Hedgehog signaling, inflammatory pathways, and pathways mediating paracrine interactions between epithelial cells and their microenvironment, which are crucial for the formation and maintenance of the fibroinflammatory stroma in pancreatic cancer (Collins et al., 2012). Additionally, KRAS mutations lead to the permanent activation of the P21 RAS protein, triggering a cascade of signaling pathways that promote cellular transformation, proliferation, invasion, and survival (Bournet et al., 2016). The NF-κB pathway is also significantly influenced byKRAS mutations, with GSK-3α stabilizing the TAK1-TAB complex to promote IKK activity and noncanonical NF-κB signaling, which are essential for pancreatic cancer cell growth and survival (Bang et al., 2013). 3.2 Interaction with other oncogenes and tumor suppressor genes KRAS mutations often co-occur with alterations in other oncogenes and tumor suppressor genes, such as TP53. In pancreatic ductal adenocarcinoma (PDAC), KRAS mutations are present in 95% of tumors, and TP53 mutations co-occur in nearly 70% of cases. This interaction leads to the activation of pro-metastatic transcriptional networks through the cooperation of mutant p53 and KRAS effectors, such as CREB1, which upregulates FOXA1 and promotes Wnt/β-catenin signaling, driving metastasis (Kim et al., 2021). Furthermore, the ARF6-AMAP1 pathway is a major target of KRAS and TP53 mutations, promoting tumor invasion and immune evasion by regulating integrin and E-cadherin dynamics (Hashimoto et al., 2019). These interactions highlight the complex interplay between KRAS and other genetic alterations in driving pancreatic cancer progression.
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