Liu Ying, Jin Aihua, Quan Xianglan, Shen Xionghu, Zhou Houkun, Zhao Xingyu, Lin Zhenhua
Central Laboratory, The Affiliated Hospital of Yanbian University, Yanji, 133000, People's Republic of China.
Key Laboratory of Pathobiology (Yanbian University), State Ethnic Affairs Commission, Yanji, 133000, People's Republic of China.
Cancer Cell Int. 2023 Nov 28;23(1):301. doi: 10.1186/s12935-023-03159-3.
T lymphoma invasion and metastasis 1 (Tiam1) is a tumor related gene that specifically activates Rho-like GTPases Rac1 and plays a critical role in the progression of various malignancies. Glycolysis plays an important role in cancer progression, it is crucial for supplying energy and producing metabolic end products, which can maintain the survival of tumor cells. As yet, however, the mechanism of Tiam1 in glycolysis reprogramming of pancreatic cancer (PC) remains to be clarified. Here, we investigated the functional role of Tiam1 in PC cell proliferation, metastasis and glycolysis reprogramming. It is expected to provide a new direction for clinical treatment.
The clinical relevance of Tiam1 was evaluated in 66 patients with PC, the effect of Tiam1 on cell proliferation was detected via 5-Ethynyl-2'-deoxyuridine (EdU) and colony formation. The ability of cell migration was detected by the wound healing and Transwell. Quantitative real time polymerase chain reaction (qRT-PCR) and luciferase reporter gene experiments clarify the regulatory relationship of miR-590-5p inhibiting Tiam1. Detection of the molecular mechanism of Tiam1 regulating glucose metabolism reprogramming in PC by glucose metabolism kit. RNA sequencing and Co-Immunoprecipitation (CoIP) have identified glucose transporter protein 3 (SLC2A3) as a key downstream target gene for miR-590-5p/Tiam1.
We found that Tiam1 expression increased in PC tissues and was associated with lymph node metastasis. The silencing or exogenous overexpression of Tiam1 significantly altered the proliferation, invasion, and angiogenesis of PC cells through glucose metabolism pathway. In addition, Tiam1 could interact with the crucial SLC2A3 and promote the evolution of PC in a SLC2A3-dependent manner. Moreover, miR-590-5p was found to exacerbate the PC cell proliferation, migration and invasion by targeting Tiam1. Furthermore, the reversing effects on proliferation, migration and invasion were found in PC cells with miR-590-5p/Tiam1 overexpression after applying glucose metabolism inhibition.
Our findings demonstrate the critical role of Tiam1 in PC development and the miR-590-5p/Tiam1/SLC2A3 signaling pathway may serve as a target for new PC therapeutic strategies.
T淋巴瘤侵袭与转移1（Tiam1）是一种肿瘤相关基因，可特异性激活Rho样GTP酶Rac1，并在多种恶性肿瘤进展中起关键作用。糖酵解在癌症进展中起重要作用，对于提供能量和产生代谢终产物至关重要，这些产物可维持肿瘤细胞的存活。然而，迄今为止，Tiam1在胰腺癌（PC）糖酵解重编程中的机制仍有待阐明。在此，我们研究了Tiam1在PC细胞增殖、转移和糖酵解重编程中的功能作用。期望为临床治疗提供新方向。
对66例PC患者评估Tiam1的临床相关性，通过5-乙炔基-2'-脱氧尿苷（EdU）和集落形成检测Tiam1对细胞增殖的影响。通过伤口愈合实验和Transwell检测细胞迁移能力。定量实时聚合酶链反应（qRT-PCR）和荧光素酶报告基因实验阐明miR-590-5p抑制Tiam1的调控关系。用糖代谢试剂盒检测Tiam1调节PC中葡萄糖代谢重编程的分子机制。RNA测序和免疫共沉淀（CoIP）已确定葡萄糖转运蛋白3（SLC2A3）是miR-590-5p/Tiam1的关键下游靶基因。
我们发现Tiam1在PC组织中的表达增加，且与淋巴结转移相关。Tiam1的沉默或外源性过表达通过葡萄糖代谢途径显著改变PC细胞的增殖、侵袭和血管生成。此外，Tiam1可与关键的SLC2A3相互作用，并以SLC2A3依赖的方式促进PC的进展。此外，发现miR-590-5p通过靶向Tiam1加剧PC细胞的增殖、迁移和侵袭。此外，在应用糖代谢抑制后，在miR-590-5p/Tiam1过表达的PC细胞中发现了对增殖、迁移和侵袭的逆转作用。
我们的研究结果证明了Tiam1在PC发展中的关键作用，并且miR-590-5p/Tiam1/SLC2A3信号通路可能作为PC新治疗策略的靶点。
