Transforming growth factor-β (TGF-β) signaling is a double-edged sword in cancer development and progression. TGF-β signaling plays a tumor suppressive role during the early stages of tumor development but promotes tumor progression in later stages. We have previously identified various mutations of TGF-β receptor II (TβRII) in human oral squamous cell carcinoma (OSCC) samples. In the present study we analyzed I227T/N236D mutation of TβRII, which was detected in the metastatic lymph node of an OSCC patient. The effect of I227T/N236D TβRII mutation on transcriptional activities was measured using DR26 cells, which lack functional TβRII. HSC2 human OSCC cells stably expressing wild-type and I227T/N236D mutant TβRII were generated and used to examine the effect of I227T/N236D TβRII mutation on xenograft tumor growth, in vitro cell proliferation, apoptosis, migration, and invasion. The I227T/N236D mutation of TβRII upregulated TGF-β signaling and promoted xenograft tumor growth when compared with the wild-type, without affecting the in vitro proliferative capacities. To delineate the differences in proliferative capacities in vivo and in vitro, the apoptotic and survival signals were analyzed following curcumin treatment. Concomitant with apoptotic induction, epidermal growth factor receptor (EGFR) activation was observed upon curcumin treatment, which was further activated in I227T/N236D mutant transfectant cells when compared with wild-type cells. Enhanced EGFR activation correlated with cell survival and apoptotic resistance. Enhanced migratory and invasive capabilities of I227T/N236D mutant cells also depended on EGFR signaling. These results suggest that enhanced EGFR signaling via upregulated TGF-β signaling shifted the balance toward survival and promoted cell migration and invasion in I227T/N236D mutant cells, elucidating the role of I227T/N236D mutation of TβRII in OSCC progression.

中文翻译：

---

一种新的TGF-β受体II突变（I227T / N236D）通过增强的EGFR信号传导促进口腔鳞状细胞癌的侵袭性表型

转化生长因子-β（TGF-β）信号传导是癌症发展和进程中的一把双刃剑。TGF-β信号传导在肿瘤发展的早期阶段起着抑制肿瘤的作用，但在晚期阶段促进肿瘤的进展。我们先前已经在人口腔鳞状细胞癌（OSCC）样品中鉴定了TGF-β受体II（TβRII）的各种突变。在本研究中，我们分析了在OSCC患者的转移性淋巴结中检测到的TβRII的I227T / N236D突变。使用缺乏功能性TβRII的DR26细胞来测量I227T / N236DTβRII突变对转录活性的影响。产生稳定表达野生型和I227T / N236D突变体TβRII的HSC2人OSCC细胞，并用于检查I227T / N236DTβRII突变对异种移植瘤生长，体外细胞增殖，细胞凋亡，迁移和侵袭。与野生型相比，TβRII的I227T / N236D突变上调了TGF-β信号传导并促进了异种移植肿瘤的生长，而没有影响其体外增殖能力。为了描述体内和体外增殖能力的差异，姜黄素治疗后分析了细胞凋亡和存活信号。与凋亡诱导同时，在姜黄素处理中观察到表皮生长因子受体（EGFR）活化，与野生型细胞相比，在I227T / N236D突变型转染细胞中进一步活化。增强的EGFR激活与细胞存活和凋亡抗性相关。I227T / N236D突变细胞增强的迁移和侵袭能力也取决于EGFR信号传导。