NEIL3 and TOP2A drive esophageal cancer through WNT signaling

A Silent Killer with Limited Treatment Options

Esophageal cancer (EC) is one of the deadliest cancers, ranking among the leading causes of cancer-related deaths worldwide. It begins in the lining of the esophagus and is often diagnosed in advanced stages. Common risk factors include long-term smoking, heavy alcohol use, and exposure to harmful chemicals, all of which can damage DNA over time.

Despite medical advances, EC continues to pose challenges. Many patients respond poorly to chemotherapy or radiation, and the cancer often spreads quickly. Researchers are urgently searching for better ways to understand, detect, and treat this disease at the molecular level.

A recent study brings attention to two key molecules that may drive the growth of esophageal cancer: NEIL3 and TOP2A.

What Are NEIL3 and TOP2A?

Both NEIL3 and TOP2A are involved in the maintenance of DNA, the genetic blueprint of our cells.

• NEIL3 helps repair damaged DNA caused by oxidative stress—a type of internal cellular damage that occurs in many cancers.
• TOP2A assists in the unwinding and rewinding of DNA during cell replication, a process essential for cell growth.

These proteins are often more active in cancer cells, but their exact role in esophageal cancer wasn’t well understood—until now.

The Research Question

The scientists set out to answer a key question: How do NEIL3 and TOP2A affect esophageal cancer, and are they working together or separately?

To find out, they conducted experiments using a common esophageal cancer cell line (ECA109). In the lab, they increased the levels of NEIL3 or reduced TOP2A using specific molecular tools. Then, they observed how the cancer cells behaved.

They also studied tumors grown in mice to see if the effects would hold up in a living system.

Major Findings

1. Both NEIL3 and TOP2A Are Highly Active in Cancer Cells

Compared to normal esophageal cells, cancer cells had much higher levels of NEIL3 and TOP2A. This hints that these proteins may play a role in helping tumors grow and survive.

2. NEIL3 Makes Cancer Cells Grow Faster

When researchers increased NEIL3 levels, cancer cells:

• Grew more quickly
• Formed more colonies
• Were less likely to die through a process called apoptosis (a form of programmed cell death)

In simple terms, NEIL3 helped cancer cells become more aggressive.

3. TOP2A Is Also Important—But Works Separately

When TOP2A was turned off, the cancer cells:

• Grew more slowly
• Formed fewer colonies
• Were more likely to undergo apoptosis

Interestingly, even when NEIL3 was boosted, it couldn’t undo the damage caused by removing TOP2A. This shows the two proteins may work independently, rather than as part of a single system.

4. They Influence Cell Movement

Cancer spreads by invading nearby tissues and traveling to other parts of the body. NEIL3 made the cells more mobile and invasive. TOP2A had the opposite effect—its removal made the cells less likely to move or invade. Again, boosting NEIL3 couldn’t cancel out the effects of losing TOP2A.

The Role of the WNT Pathway

One of the key discoveries in this study involves the WNT signaling pathway—a chain of signals inside the cell that controls growth, survival, and repair.

This pathway is often overly active in cancers, leading to uncontrolled cell growth. The researchers found:

• NEIL3 increased levels of important WNT-related proteins, including β-catenin, TCF, and cyclin D1—all known to encourage cancer cell growth.
• TOP2A knockdown led to lower levels of these proteins.
• Other proteins related to tumor suppression, like p53 and ubiquitin, responded in complex ways, with NEIL3 reducing them and TOP2A knockdown increasing them.

Although NEIL3 influenced several aspects of this pathway, it still couldn’t fully restore normal function when TOP2A was missing.

Confirmed in Mice: NEIL3 Fuels Tumor Growth

To validate their findings, the team implanted human cancer cells with reduced NEIL3 into mice. Tumors grew much slower in these mice. They were also smaller and lighter.

Inside the tumors, levels of WNT-related proteins dropped, and levels of tumor-suppressing proteins like p53 rose. This confirmed that NEIL3 helps esophageal tumors grow, at least in part by activating the WNT pathway.

Why This Matters

This research offers two important insights:

1. NEIL3 and TOP2A both play key roles in esophageal cancer, but they seem to operate in parallel rather than directly influencing each other.
2. Targeting these proteins could offer new ways to treat esophageal cancer, especially by disrupting the WNT signaling pathway.

While this study used only one cell line, the findings are promising and point toward future studies in other models and, eventually, in patients.

“NEIL3 and TOP2A play key roles in EC progression through the WNT signaling pathway,” the authors note. “Targeting these molecules may offer promising therapeutic strategies.”

Looking Ahead

For scientists and clinicians, these findings represent a potential shift in how we approach treatment. Instead of focusing solely on traditional chemotherapy, which can be ineffective or toxic, future therapies could aim to specifically block NEIL3 or TOP2A, or interfere with the WNT pathway they influence.

Further studies will be needed to:

• Validate these results in other esophageal cancer models
• Explore whether drugs targeting NEIL3 or TOP2A are safe and effective
• Understand how these proteins interact with other cancer-related pathways

But the path is clearer now.

Final Thoughts

Understanding how esophageal cancer grows at the molecular level is essential for developing better treatments. By identifying NEIL3 and TOP2A as important drivers—especially through their effects on the WNT signaling pathway—this research opens new doors.

As scientists work toward more targeted, less toxic therapies, studies like this bring hope for improved outcomes in a disease where new strategies are urgently needed.

 

The translation of the preceding English text in Chinese:

 

一个治疗手段有限的无声杀手

食管癌（Esophageal Cancer，EC）是最致命的癌症之一，在全球癌症相关死亡原因中名列前茅。它起始于食管内壁，并且常在晚期才被诊断出来。常见的风险因素包括长期吸烟、大量饮酒以及暴露于有害化学物质，这些因素会随着时间推移损伤DNA。

尽管医学不断进步，食管癌仍然是一项挑战。许多患者对化疗或放疗反应不佳，且癌症往往迅速扩散。研究人员正在紧急寻找在分子水平上更好地理解、检测和治疗这种疾病的方法。

最近的一项研究聚焦于两种可能驱动食管癌生长的关键分子：NEIL3 和 TOP2A。

什么是 NEIL3 和 TOP2A？

NEIL3 和 TOP2A 都参与DNA的维护工作——DNA是细胞的遗传蓝图。

• NEIL3 有助于修复由氧化应激引起的DNA损伤——这是一种在许多癌症中常见的细胞内部损伤。

• TOP2A 在细胞复制过程中帮助DNA的解旋与重组，这一过程对细胞生长至关重要。

这些蛋白质在癌细胞中常常表现得更加活跃，但它们在食管癌中的具体作用此前尚不清楚——直到这项研究的出现。

研究问题

科学家们试图解答一个关键问题：NEIL3 和 TOP2A 如何影响食管癌？它们是协同作用还是各自独立？

为此，他们在实验室中使用常见的食管癌细胞系（ECA109）进行实验。他们使用特定的分子工具增加 NEIL3 的表达或降低 TOP2A 的表达，然后观察癌细胞的行为变化。

他们还研究了在小鼠中生长的肿瘤，以验证这些效应在活体系统中是否仍然成立。

主要发现

NEIL3 和 TOP2A 在癌细胞中高度活跃

与正常食管细胞相比，癌细胞中的 NEIL3 和 TOP2A 水平均显著升高，这暗示它们可能在帮助肿瘤生长和存活中起作用。

NEIL3 让癌细胞生长得更快

当研究人员提高 NEIL3 水平时，癌细胞表现出以下特征：

• 生长速度加快

• 形成更多细胞集落

• 更不容易经历程序性细胞死亡（凋亡）

简单来说，NEIL3 使癌细胞变得更具攻击性。

TOP2A 也很重要，但作用独立

当 TOP2A 被抑制时，癌细胞：

• 生长速度减慢

• 形成的集落更少

• 更容易发生凋亡

有趣的是，即使提高了 NEIL3，也无法弥补移除 TOP2A 所造成的影响。这表明这两个蛋白质可能是独立工作的，而不是一个统一系统的一部分。

它们影响细胞迁移能力

癌症的扩散方式是入侵邻近组织并传播到身体其他部位。NEIL3 使癌细胞更容易移动和侵袭，而去除 TOP2A 则使细胞不易迁移或侵袭。同样地，提高 NEIL3 水平无法抵消失去 TOP2A 带来的影响。

WNT 信号通路的作用

该研究的一个关键发现涉及 WNT 信号通路——这是细胞内部控制生长、生存和修复的一系列信号传导机制。

这个通路在癌症中常常过度活跃，导致细胞无法控制地增长。研究人员发现：

• NEIL3 会增加几个与 WNT 通路相关的重要蛋白的水平，包括 β-连环蛋白（β-catenin）、TCF 和 Cyclin D1——这些都是已知的促癌因子。

• 抑制 TOP2A 会降低这些蛋白的水平。

• 一些与肿瘤抑制相关的蛋白（如 p53 和泛素）也表现出复杂反应——NEIL3 会减少它们，而抑制 TOP2A 则增加它们的表达。

尽管 NEIL3 影响了该通路的多个方面，但在缺少 TOP2A 的情况下，NEIL3 仍无法完全恢复其正常功能。

在小鼠中验证：NEIL3 促进肿瘤生长

为了验证研究结果，研究团队将缺乏 NEIL3 的人类癌细胞植入小鼠体内。结果发现，这些小鼠体内的肿瘤生长显著变慢，肿瘤也更小、更轻。

肿瘤内部，WNT 相关蛋白水平下降，而像 p53 这样的肿瘤抑制蛋白水平升高。这进一步证实，NEIL3 至少部分是通过激活 WNT 通路来促进食管肿瘤生长的。

研究意义

这项研究带来了两个重要的启示：

1. NEIL3 和 TOP2A 在食管癌中都扮演着关键角色，但它们似乎是并行工作的，而不是彼此直接作用。

2. 靶向这些蛋白可能为治疗食管癌带来新的方法，特别是通过干扰它们影响的 WNT 信号通路。

虽然本研究仅使用一种细胞系，但其发现具有前景，指向未来在其他模型乃至临床患者中的进一步研究。

“NEIL3 和 TOP2A 通过 WNT 信号通路在食管癌发展中发挥关键作用，”作者指出。“靶向这些分子可能提供有前景的治疗策略。”

展望未来

对科学家和临床医生来说，这些发现可能标志着治疗策略的转变。未来的疗法可能不再仅依赖传统的化疗（其效果有限且毒副作用大），而是针对 NEIL3 或 TOP2A，或者阻断它们所影响的 WNT 通路。

后续研究需要：

• 在其他食管癌模型中验证这些结果

• 探索靶向 NEIL3 或 TOP2A 的药物是否安全有效

• 进一步理解这些蛋白与其他癌症相关通路的互作机制

但现在，前路更加清晰。

结语

理解食管癌在分子层面的生长机制，是开发更有效治疗手段的关键。通过确认 NEIL3 和 TOP2A 作为关键驱动因子，尤其是在它们对 WNT 信号通路的影响方面，这项研究为新的治疗方向打开了大门。

在科学家努力开发更具针对性、毒性更小的治疗手段的同时，这类研究带来了希望——为一种亟需新策略的疾病提供了改善预后的可能。

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Reference:

Hui Li, Panpan Wang, Huijuan Chen, Yanyan Shao, Hui Luo

NEIL3 and TOP2A as key drivers of esophageal cancer through WNT signaling.

Biomol Biomed [Internet]. 2025 Jan. 29 [cited 2025 Apr. 7];

Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/11365

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