Singh Sajal Raj, Bhaskar Rakesh, Ghosh Shampa, Yarlagadda Bhuvaneshwar, Singh Krishna Kumar, Verma Prashant, Sengupta Sonali, Mladenov Mitko, Hadzi-Petrushev Nikola, Stojchevski Radoslav, Sinha Jitendra Kumar, Avtanski Dimiter
GloNeuro, Sector 107, Vishwakarma Road, Noida 201301, India.
School of Chemical Engineering, Yeungnam University, Gyeongsan-si 38541, Republic of Korea.
Cancers (Basel). 2025 Mar 24;17(7):1082. doi: 10.3390/cancers17071082.
Cancer is complex because of the critical imbalance in genetic regulation as characterized by both the overexpression of oncogenes (OGs), mainly through mutations, amplifications, and translocations, and the inactivation of tumor-suppressor genes (TSGs), which entail the preservation of genomic integrity by inducing apoptosis to counter the malignant growth. Reviewing the intricate molecular interplay between OGs and TSGs draws attention to their cell cycle, apoptosis, and cancer metabolism regulation. In the present review, we discuss seminal discoveries, such as Knudson's two-hit hypothesis, which framed the field's understanding of cancer genetics, leading to the next breakthroughs with next-generation sequencing and epigenetic profiling, revealing novel insights into OG and TSG dysregulation with opportunities for targeted therapy. The key pathways, such as MAPK/ERK, PI3K/AKT/mTOR, and Wnt/β-catenin, are presented in the context of tumor progression. Importantly, we further highlighted the advances in therapeutic strategies, including inhibitors of KRAS and MYC and restoration of TSG function, despite which mechanisms of resistance and tumor heterogeneity pose daunting challenges. A high-level understanding of interactions between OG-TSGs forms the basis for effective, personalized cancer treatment-something to strive for in better clinical outcomes. This synthesis should integrate foundational biology with translation and, in this case, contribute to the ongoing effort against cancer.
癌症很复杂，因为其基因调控存在严重失衡，表现为癌基因（OGs）主要通过突变、扩增和易位过度表达，以及肿瘤抑制基因（TSGs）失活，肿瘤抑制基因通过诱导细胞凋亡来维持基因组完整性以对抗恶性生长。回顾OGs和TSGs之间复杂的分子相互作用，会让人关注它们在细胞周期、细胞凋亡和癌症代谢调控方面的作用。在本综述中，我们讨论了一些重大发现，比如克努森的二次打击假说，该假说奠定了该领域对癌症遗传学的理解基础，随后随着下一代测序和表观遗传学分析取得进一步突破，揭示了OG和TSG失调的新见解，为靶向治疗带来了机会。关键信号通路，如MAPK/ERK、PI3K/AKT/mTOR和Wnt/β-连环蛋白，在肿瘤进展的背景下进行了阐述。重要的是，我们进一步强调了治疗策略的进展，包括KRAS和MYC抑制剂以及TSG功能的恢复，尽管耐药机制和肿瘤异质性带来了严峻挑战。对OG-TSGs之间相互作用的深入理解构成了有效、个性化癌症治疗的基础，这是为实现更好临床结果而努力的方向。这种综合应将基础生物学与转化研究相结合，在这种情况下，有助于当前对抗癌症的努力。
