Saif Muhammad Wasif, Chang Wen-Han, Myers Scott, Potts Michael, Qazi Sanjive, Trieu Vuong
Karmanos Cancer Institute, 4100 John R Street, HW04HO, Detroit, MI 48201, USA.
Oncotelic Therapeutics, 29397 Agoura Road, Suite 107, Agoura Hills, CA 91301, USA.
Int J Mol Sci. 2025 Jul 1;26(13):6357. doi: 10.3390/ijms26136357.
Transforming growth factor-beta (TGF-β) exhibits dual roles in pancreatic ductal adenocarcinoma (PDAC), acting as a tumor suppressor in early stages and a tumor promoter in later disease. Among the three isoforms, TGFB2 is particularly associated with poor prognosis and aggressive phenotypes. This study evaluated the prognostic significance of TGFB2 mRNA and methylation levels in PDAC, with an emphasis on age-dependent effects. Bioinformatic analyses revealed that high TGFB2 expression was significantly associated with reduced overall survival (OS) in patients under 65 (TGFB2 high vs. low median OS: 17.9 vs. 66.9 months) but not in older cohorts. IL6 expression, a downstream target of TGF-β, followed a similar survival profile. Moreover, elevated methylation showed improved survival in younger patients (high methylation vs. low methylation median OS: 66.9 vs. 17.9 months). In addition, our clinical data from a PDAC trial using OT-101, an antisense oligonucleotide targeting TGFB2, further supported these findings-young patients treated with OT-101 showed improved OS compared to untreated controls. Notably, the methylation of also correlated with better OS in young patients. These results demonstrate the importance of TGFB2 as both a prognostic biomarker and therapeutic target in younger PDAC patients and further suggest that epigenetic modulation plays a key role in TGF-β signaling in pancreatic cancer progression. Our study emphasizes the isoform- and age-specific prognostic significance of TGFB2 in PDAC and supports the potential insights provided through methylation and expression profiling for personalized treatment strategies, particularly for younger patients who may benefit most from TGFB2-targeted therapies.
转化生长因子-β（TGF-β）在胰腺导管腺癌（PDAC）中具有双重作用，在疾病早期起肿瘤抑制作用，而在疾病后期起肿瘤促进作用。在三种异构体中，TGFB2 尤其与预后不良和侵袭性表型相关。本研究评估了 TGFB2 mRNA 和甲基化水平在 PDAC 中的预后意义，重点关注年龄依赖性效应。生物信息学分析显示，TGFB2 高表达与 65 岁以下患者的总生存期（OS）降低显著相关（TGFB2 高表达组与低表达组的中位 OS：17.9 个月 vs. 66.9 个月），而在老年队列中则不然。TGF-β 的下游靶点 IL6 的表达呈现相似的生存模式。此外，甲基化水平升高在年轻患者中显示出更好的生存期（高甲基化组与低甲基化组的中位 OS：66.9 个月 vs. 17.9 个月）。此外，我们来自一项使用靶向 TGFB2 的反义寡核苷酸 OT-101 的 PDAC 试验的临床数据进一步支持了这些发现——与未治疗的对照组相比，接受 OT-101 治疗的年轻患者的 OS 有所改善。值得注意的是， 的甲基化在年轻患者中也与更好的 OS 相关。这些结果证明了 TGFB2 作为年轻 PDAC 患者预后生物标志物和治疗靶点的重要性，并进一步表明表观遗传调控在胰腺癌进展中的 TGF-β 信号传导中起关键作用。我们的研究强调了 TGFB2 在 PDAC 中的异构体和年龄特异性预后意义，并支持通过甲基化和表达谱分析为个性化治疗策略提供的潜在见解，特别是对于可能从靶向 TGFB2 治疗中获益最大的年轻患者。
