Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan.
Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan.
World J Surg Oncol. 2022 Sep 10;20(1):291. doi: 10.1186/s12957-022-02747-3.
SMAD4 is a key mediator of TGFβ signaling and one of the mutated genes in extrahepatic bile duct cancer (eBDC). It has been also reported that SMAD4 has dual functions, in carcinogenesis via silencing and in tumor invasion/metastasis via signaling, depending on tumor stage. We previously visualized more nuclear transitioning functional SMAD4 at the tumor invasion front than the central lesion. So, we investigated the localization of functional SMAD4 (e.g., invasion area or metastasis lesion) and its association with chemotherapy and chemo-radiation therapy.
We performed SMAD4 immunostaining on 98 resected eBDC specimens and evaluated the presence of the functional form of nuclear SMAD4 at the central lesion, invasion front, and metastatic lymph node. We also examined the influence on chemotherapy after recurrence (n = 33) and neoadjuvant chemo-radiation therapy (NAC-RT, n = 21) and the prognostic value of using retrospective data.
In 73 patients without NAC-RT, 8.2% had loss of SMAD4 expression and 23.3% had heterogeneous expression. Patients without SMAD4 expression at any site had significantly poorer overall survival (OS) than other patients (P = 0.014). Expression of SMAD4 at the invasion front was related to better survival (recurrence-free survival [RFS] P = 0.033; OS P = 0.047), and no SMAD4 expression at the metastatic lymph node was related to poorer OS (P = 0.011). The patients who had high SMAD4 expression had poorer prognosis after recurrence (RFS P = 0.011; OS P = 0.056). At the residual cancer in the resected specimen, SMAD4 was highly expressed after NAC-RT (P = 0.039).
Loss of SMAD4 protein expression was a poor prognostic factor in eBDC at resectable stage. However, the intensity of functional SMAD4 in eBDC is a marker of resistance to chemo-radiotherapy and malignant potential at advanced stages.
SMAD4 是 TGFβ 信号转导的关键介质，也是肝外胆管癌（eBDC）中突变的基因之一。据报道，SMAD4 具有双重功能，取决于肿瘤阶段，在致癌作用中通过沉默，在肿瘤侵袭/转移中通过信号转导。我们之前在肿瘤侵袭前沿观察到更多核转位功能 SMAD4，而在中央病变中则较少。因此，我们研究了功能 SMAD4 的定位（例如侵袭区或转移病灶）及其与化疗和放化疗的关系。
我们对 98 例切除的 eBDC 标本进行 SMAD4 免疫组化染色，评估中央病变、侵袭前沿和转移性淋巴结中功能性核 SMAD4 的存在。我们还检查了复发后（n=33）和新辅助放化疗（NAC-RT，n=21）后化疗的影响，并利用回顾性数据检查了预后价值。
在没有 NAC-RT 的 73 例患者中，8.2%的患者 SMAD4 表达缺失，23.3%的患者表达异质性。任何部位无 SMAD4 表达的患者总生存（OS）明显较差（P=0.014）。侵袭前沿的 SMAD4 表达与生存相关（无复发生存[RFS] P=0.033；OS P=0.047），而转移淋巴结无 SMAD4 表达与 OS 较差相关（P=0.011）。在接受 NAC-RT 后，高 SMAD4 表达的患者复发后的预后较差（RFS P=0.011；OS P=0.056）。在切除标本中的残留癌中，NAC-RT 后 SMAD4 高表达（P=0.039）。
在可切除阶段的 eBDC 中，SMAD4 蛋白表达缺失是预后不良的因素。然而，eBDC 中功能性 SMAD4 的强度是化疗和放疗抵抗和晚期恶性潜能的标志物。
