Xiao Tianxian, Wei Fangze, Zhou Sicheng, Zhao Fuqiang, Huang Fei, Qian Liu
Department of Colorectal Surgery, National Cancer Center / National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Breast Disease Center, Peking University First Hospital, Beijing, 100034, China.
Cancer Immunol Immunother. 2025 May 13;74(7):199. doi: 10.1007/s00262-025-03991-8.
Rectal cancer accounts for approximately 40% of colorectal cancer cases, and lateral pelvic lymph node (LPLN) metastasis in rectal cancer significantly increases the local recurrence rate. Despite its clinical significance, studies on the molecular biology of LPLN metastasis are relatively scarce. In this study, we aimed to elucidate the underlying mechanisms by identifying hub regulatory genes in LPLN tissues and analyzing differentially expressed genes shared between tumor and pericarcinomatous tissues within our clinical cohort. To investigate the biological functions of these hub regulatory genes, we performed GSEA, GO, and KEGG pathway analyses on mRNA-Seq data. Among the identified hub genes, KLF12 emerged as a pivotal regulatory gene in rectal cancer. We further explored its clinical relevance and biological function. Our findings, validated using public databases, clinical cohort data, and immunohistochemistry (IHC), identified KLF12 as a specific marker for LPLN. Additionally, KLF12 expression exhibited a strong correlation with disease-free survival (DFS). According to clinical data, significant differences in KLF12 expression exist between groups based on factors such as age, gender, tumor location, pathological N stage, and postoperative tumor residue. Both treatment outcomes (DFS) and receiver operating characteristic curves (AUCs) were significantly associated with KLF12 expression. Furthermore, KLF12 demonstrated a strong association with immune cell infiltration, immune checkpoint expression, and immunophenoscore (IPS), indicating its potential regulatory role in immunotherapy. Functional molecular experiments revealed that KLF12 overexpression inhibited the proliferation, migration, and invasion of SW620 cells. In conclusion, leveraging mRNA-Seq data, TCGA database analysis, immune infiltration data, and biological function assessments, we confirmed that KLF12 could serve as an effective predictive marker and potential therapeutic target for LPLN metastasis. These findings suggest that KLF12 may be instrumental in assessing predictive risk and identifying novel therapeutic targets for patients with rectal cancer.
直肠癌约占结直肠癌病例的40%，直肠癌的侧方盆腔淋巴结（LPLN）转移显著增加局部复发率。尽管其具有临床意义，但关于LPLN转移分子生物学的研究相对较少。在本研究中，我们旨在通过鉴定LPLN组织中的枢纽调控基因并分析我们临床队列中肿瘤组织与癌旁组织之间共享的差异表达基因，来阐明其潜在机制。为了研究这些枢纽调控基因的生物学功能，我们对mRNA-Seq数据进行了基因集富集分析（GSEA）、基因本体（GO）和京都基因与基因组百科全书（KEGG）通路分析。在鉴定出的枢纽基因中，KLF12成为直肠癌中的关键调控基因。我们进一步探索了其临床相关性和生物学功能。我们使用公共数据库、临床队列数据和免疫组织化学（IHC）验证了我们的发现，确定KLF12是LPLN的特异性标志物。此外，KLF12表达与无病生存期（DFS）呈强相关。根据临床数据，基于年龄、性别、肿瘤位置、病理N分期和术后肿瘤残留等因素，各亚组之间KLF12表达存在显著差异。治疗结果（DFS）和受试者工作特征曲线（AUC）均与KLF12表达显著相关。此外，KLF12与免疫细胞浸润、免疫检查点表达和免疫表型评分（IPS）密切相关，表明其在免疫治疗中具有潜在调控作用。功能分子实验表明，KLF12过表达抑制SW620细胞的增殖、迁移和侵袭。总之，通过利用mRNA-Seq数据、TCGA数据库分析、免疫浸润数据和生物学功能评估，我们证实KLF12可作为LPLN转移的有效预测标志物和潜在治疗靶点。这些发现表明，KLF12可能有助于评估直肠癌患者的预测风险并确定新的治疗靶点。
