A new study reveals how the transcription factor TCF12 promotes angiogenesis and limits the effectiveness of sorafenib in liver cancer by stabilizing HIF-1α.
Understanding Liver Cancer and Its Treatment Challenges
Liver cancer remains one of the most lethal cancers globally. In 2022 alone, more than 860,000 new cases were reported, with around 750,000 deaths. Despite being only the sixth most common cancer, its high mortality rate is a serious concern. This is mainly because liver cancer typically develops without obvious symptoms and is often diagnosed at an advanced stage, when treatment options are limited.
Current approaches for advanced liver cancer include interventional therapy and targeted drugs. Anti-angiogenic therapies—those that target blood vessel formation—are among the key strategies used to slow disease progression. One of the most commonly used drugs is sorafenib, a multi-kinase inhibitor that blocks vascular endothelial growth factor receptors (VEGFRs). While sorafenib can improve progression-free survival by about three months, it rarely extends overall survival significantly. Furthermore, only about 30% of patients respond to the drug, and most develop resistance within six months.
One major driver of this resistance is tumor hypoxia, a condition that arises as anti-angiogenic therapy cuts off oxygen supply. This environment triggers the activation of hypoxia-inducible factors (HIFs), especially HIF-1α, which in turn drives the expression of pro-angiogenic genes and helps tumors adapt and survive.
A New Player in Tumor Vascularization: TCF12
The protein TCF12, a member of the basic helix-loop-helix (bHLH) family of transcription factors, is increasingly gaining attention in cancer research. It has been implicated in various processes like cell growth, differentiation, and metastasis. In liver cancer, previous research suggested that TCF12 enhances endothelial cell functions such as lumen formation and migration.
However, until now, the molecular mechanisms connecting TCF12 to blood vessel formation and drug resistance in liver cancer were poorly understood.
The Study: Mapping the Role of TCF12
A research team from Nantong University and The Second People’s Hospital of Nantong aimed to fill this gap. They conducted a multi-level investigation, combining bioinformatics analysis, laboratory experiments, and clinical tissue samples, to determine how TCF12 affects angiogenesis and the effectiveness of sorafenib in liver cancer.
Using 374 tumor samples from the TCGA-LIHC dataset and 50 patient samples from clinical settings, the team assessed TCF12 expression and its relationship to patient survival. They also conducted functional assays—including migration, tube formation, and endothelial cell permeability tests—to examine how TCF12 affects endothelial behavior.
Their main goal was to understand whether TCF12 works through HIF-1α, a known driver of hypoxia response and vascularization.
Key Findings
1. TCF12 Is Overexpressed in Liver Cancer
Data from the TCGA database and patient tissue samples confirmed that TCF12 is significantly upregulated in liver cancer tissues compared to normal tissues. This trend was consistent across various tumor grades and stages. Patients with higher TCF12 levels had shorter progression-free intervals and overall survival, especially those with more aggressive or advanced disease.
2. TCF12 Drives Angiogenesis
In vitro experiments showed that endothelial cells with high TCF12 expression had enhanced migration, tube formation, and permeability—key features of angiogenesis. Conversely, knocking down TCF12 led to reduced vascular activity.
Immunohistochemistry also revealed a positive correlation between TCF12 and CD31, a marker for microvessel density, further confirming TCF12’s role in blood vessel formation.
3. TCF12 Reduces Sorafenib Sensitivity
One of the most striking findings was that cells with reduced TCF12 expression became more sensitive to sorafenib. In contrast, overexpression of HIF-1α reversed this effect, restoring the cells’ resistance to the drug.
4. TCF12 Stabilizes HIF-1α
Both TCF12 and HIF-1α are bHLH proteins capable of dimerizing with other transcription factors. Through co-immunoprecipitation experiments, the researchers confirmed a direct interaction between the two. TCF12 was found to stabilize HIF-1α levels, allowing the latter to accumulate and activate its downstream targets even under normoxic conditions.
This interaction appears central to how TCF12 promotes both angiogenesis and drug resistance.
Why This Matters
These findings highlight TCF12 as a dual regulator of tumor growth: it drives the formation of new blood vessels and enables resistance to a first-line drug, sorafenib. By stabilizing HIF-1α, TCF12 ensures that liver tumors can survive and thrive even under conditions meant to suppress them.
This study also raises important questions about the effectiveness of current anti-angiogenic therapies. Many such treatments are tested using normal endothelial cells, which may not reflect the altered behavior of tumor-derived endothelial cells. The researchers addressed this by developing immortalized liver cancer vascular endothelial cells (ECDHCC-1), providing a more realistic model for future drug screening.
Practical Implications
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Therapeutic Targeting: TCF12 could be a novel therapeutic target for liver cancer. Inhibiting its expression may suppress angiogenesis and enhance the efficacy of existing drugs like sorafenib.
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Combination Therapy: The results suggest that combining TCF12-targeted treatments with sorafenib could potentially overcome resistance and improve patient outcomes.
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Biomarker Potential: Given its correlation with prognosis, TCF12 might also serve as a biomarker to stratify patients and tailor treatments.
Looking Ahead
While the study offers strong preclinical evidence, further work is needed to validate these findings in animal models and eventually in clinical trials. The researchers propose exploring the downstream pathways of HIF-1α, such as those involving miR-210, which could add more layers to the therapeutic strategy.
Additionally, investigating whether TCF12 contributes to acquired resistance—not just baseline resistance—could expand its relevance in long-term liver cancer management.
Conclusion
This study positions TCF12 as a key regulator of vascularization and drug response in liver cancer, working through HIF-1α stabilization. Targeting this axis may provide new avenues to combat sorafenib resistance and improve treatment outcomes for liver cancer patients.
The translation of the preceding English text in Chinese:
一项新研究揭示转录因子TCF12如何通过稳定HIF-1α促进肝癌血管生成并限制索拉非尼疗效
了解肝癌及其治疗挑战
肝癌仍是全球最致命的癌症之一。仅在2022年，就报告了超过86万例新发病例，并有约75万人因此死亡。尽管肝癌仅为第六常见癌种，但其极高的死亡率令人担忧。这主要是因为肝癌通常在无明显症状的情况下发展，确诊时已是晚期，治疗选择受限。
目前对于晚期肝癌的治疗方法包括介入治疗和靶向药物。抗血管生成疗法——即针对新生血管形成的治疗——是减缓疾病进展的关键策略之一。其中最常用的药物是索拉非尼，一种多靶点激酶抑制剂，能够阻断血管内皮生长因子受体（VEGFR）。虽然索拉非尼可以将无进展生存期延长约三个月，但很少显著延长总生存期。此外，只有约30%的患者对其有反应，大多数人在六个月内便产生耐药。
造成这种耐药的一个主要原因是肿瘤缺氧。由于抗血管生成治疗切断了氧气供应，肿瘤处于缺氧状态，进而激活缺氧诱导因子（HIF），尤其是HIF-1α，它驱动促血管生成基因的表达，使肿瘤得以适应和存活。
肿瘤血管新生中的新成员：TCF12
TCF12是一种基本螺旋-环-螺旋（bHLH）家族的转录因子，在癌症研究中日益受到关注。它已被发现与细胞生长、分化和转移等过程相关。在肝癌中，已有研究表明TCF12可增强内皮细胞的管腔形成和迁移能力。
然而，TCF12在血管生成与肝癌耐药之间的分子机制此前尚不明确。
本研究：描绘TCF12的作用机制
南通大学和南通市第二人民医院的研究团队试图填补这一知识空白。他们通过多层次研究方法，包括生物信息学分析、实验室功能试验以及临床组织样本，系统评估TCF12在肝癌血管生成和索拉非尼疗效中的作用。
研究团队分析了TCGA-LIHC数据库中的374例肿瘤样本和50例临床患者样本，评估TCF12表达与患者生存之间的关系。他们还进行了功能实验，包括迁移、管腔形成和内皮细胞通透性实验，以观察TCF12对内皮行为的影响。
研究的核心目标是确定TCF12是否通过HIF-1α这一已知缺氧反应和血管生成关键因子发挥作用。
关键发现
1. TCF12在肝癌中高表达
TCGA数据库和临床样本数据显示，TCF12在肝癌组织中明显高于正常组织。这一趋势在不同肿瘤分级和分期中均一致。TCF12表达水平高的患者，其无进展生存期和总生存期均较短，尤其是在晚期或侵袭性强的病例中更为显著。
2. TCF12促进血管生成
体外实验表明，高表达TCF12的内皮细胞具有更强的迁移、管腔形成和通透性能力，这些都是血管生成的典型特征。相反，敲低TCF12表达可显著抑制血管活性。
免疫组织化学分析也显示，TCF12与微血管密度标志物CD31呈正相关，进一步支持其促血管生成作用。
3. TCF12降低索拉非尼敏感性
最引人注目的发现之一是：敲低TCF12表达后，细胞对索拉非尼更加敏感。相反，过表达HIF-1α可逆转这一效果，使细胞恢复对药物的耐受性。
4. TCF12稳定HIF-1α
TCF12和HIF-1α均为bHLH结构蛋白，能够与其他转录因子二聚化。共免疫沉淀实验证实两者之间存在直接相互作用。TCF12可稳定HIF-1α蛋白水平，使其即使在常氧条件下也能积聚并激活下游靶基因的表达。
这种相互作用正是TCF12促进血管生成和耐药的关键机制。
研究意义
这项研究明确指出TCF12是肿瘤发展的双重调控因子：一方面促进新生血管形成，另一方面增强对一线药物索拉非尼的耐药性。通过稳定HIF-1α，TCF12确保肿瘤即使在受到治疗抑制的条件下也能存活并持续生长。
研究还提出了对当前抗血管生成疗法有效性的质疑。许多治疗是在正常内皮细胞模型中开发和测试的，可能无法真实反映来源于肿瘤的内皮细胞行为。为此，研究团队开发了永生化肝癌内皮细胞系（ECDHCC-1），为未来的药物筛选提供了更具代表性的模型。
实际应用前景
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治疗靶点：TCF12可作为新的肝癌治疗靶点。抑制其表达可能抑制血管生成，并增强索拉非尼等现有药物的疗效。
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联合治疗：研究结果表明，TCF12靶向治疗与索拉非尼联合使用可能有助于克服耐药，提高治疗效果。
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生物标志物潜力：由于TCF12表达水平与患者预后密切相关，它或可作为肝癌风险分层和个体化治疗的生物标志物。
展望未来
尽管本研究提供了有力的临床前证据，仍需在动物模型和临床试验中进一步验证这些发现。研究人员建议进一步探索HIF-1α的下游通路，例如miR-210介导的信号机制，以拓展治疗策略。
此外，研究还应考察TCF12是否参与获得性耐药（非初始耐药），这将有助于提升其在长期肝癌管理中的临床价值。
结论
本研究将TCF12定位为调控肝癌血管生成和药物反应的关键因子，其机制是通过稳定HIF-1α实现的。靶向这一通路可能为克服索拉非尼耐药、改善肝癌患者治疗效果开辟新途径。
Reference:
Yuanbin Chen, Xiaolong Wang, Jin Chen, Min Dai, Xinyue Zhang, Jie Yin, Xiao He
TCF12 enhances angiogenesis and affects sorafenib response in liver cancer via HIF-1α interaction.
Biomol Biomed [Internet]. 2025 Apr. 4 [cited 2025 May 29];
Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/12022
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