Understanding Lung Adenocarcinoma: A Silent Killer
Lung cancer continues to be the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 80–85% of all cases, with lung adenocarcinoma (LUAD) being the most common subtype. LUAD is particularly dangerous because it often progresses without symptoms, making early detection rare. Many patients are diagnosed at advanced stages, which significantly limits treatment options and leads to poor survival outcomes.
Although advances in targeted therapies and immunotherapies have improved outcomes for some LUAD patients, challenges remain. A significant number of patients do not respond to immunotherapies, and those who benefit from targeted drugs often develop resistance over time. As a result, researchers are actively searching for new molecular targets to better understand and combat LUAD.
The Role of CACYBP in LUAD
One protein attracting recent attention is calcyclin-binding protein (CACYBP). CACYBP is a multidomain adaptor protein involved in various cellular functions, including protein degradation, cell cycle regulation, and cytoskeletal organization. Prior studies have shown that CACYBP plays different roles across cancer types—promoting tumor growth in some (like liver and prostate cancers) while suppressing it in others (such as breast and renal cancers).
Despite its established role in other cancers, the exact function of CACYBP in LUAD has remained unclear—until now.
New Insights: CACYBP as a Tumor Promoter in LUAD
In a new study published in Biomolecules and Biomedicine, researchers from Southern Medical University and other institutions explored the expression and biological effects of CACYBP in LUAD. By analyzing RNA-seq data from The Cancer Genome Atlas (TCGA), the team found that CACYBP was significantly overexpressed in LUAD tumor tissues compared to normal lung tissues.
Further analysis showed that high CACYBP expression was associated with advanced tumor stage and poorer overall survival in patients. This observation was supported by immunohistochemical staining of clinical tissue samples, which revealed elevated CACYBP protein levels in LUAD tumors.
Laboratory Experiments Confirm CACYBP’s Role
To investigate how CACYBP affects tumor behavior, researchers used genetic tools to “silence” the gene in LUAD cell lines (A549 and NCI-H1299). These experiments showed that reducing CACYBP levels slowed down cell growth, limited their ability to migrate, and increased apoptosis (programmed cell death). This finding was consistent in both in vitro assays and in vivo mouse models.
Tumors formed by CACYBP-silenced cells in mice were smaller and showed reduced expression of Ki-67, a marker of cell proliferation. Together, these results confirmed that CACYBP promotes LUAD progression and could be a potential therapeutic target.
The CDK1 Connection: A Key Mechanism Identified
Digging deeper into the molecular mechanisms, the team identified cyclin-dependent kinase 1 (CDK1) as a critical downstream target of CACYBP. CDK1 is well-known for its role in driving cells through the cell cycle and enabling cell division.
RNA-sequencing of LUAD cells with and without CACYBP revealed over 1,800 differentially expressed genes. Among these, CDK1 stood out due to its central role in cell proliferation. Immunohistochemistry confirmed that CDK1 was highly expressed in LUAD tissues, mirroring CACYBP expression. A co-immunoprecipitation (co-IP) assay showed that CACYBP directly interacts with CDK1, indicating a direct regulatory link.
CDK1 Overexpression Reverses Tumor Suppression
To further test the functional relationship, researchers overexpressed CDK1 in LUAD cells where CACYBP had been silenced. The results were striking: CDK1 overexpression restored the cancerous behaviors that had been suppressed by CACYBP knockdown. Specifically, it increased cell proliferation and migration, and decreased apoptosis.
This demonstrated that CDK1 plays a key role in mediating the oncogenic effects of CACYBP in LUAD.
Involvement of the PI3K/AKT Pathway
Using pathway analysis, the team found that the PI3K/AKT signaling pathway was significantly inhibited when CACYBP was silenced. This pathway is well-known for its role in cell survival, growth, and resistance to cancer therapies.
To confirm the link between CDK1 and the PI3K/AKT pathway, the researchers treated LUAD cells with a PI3K inhibitor (LY294002). The treatment reversed the growth-promoting effects of CDK1, confirming that CDK1 exerts its function partly through PI3K/AKT signaling.
Implications for LUAD Research and Treatment
This study reveals a previously underexplored mechanism in LUAD. The CACYBP–CDK1–PI3K/AKT axis appears to be a key driver of tumor progression.
“These findings support our hypothesis that CDK1 may contribute to the tumorigenic potential of LUAD cells, at least in part, through the PI3K/AKT pathway,” the authors wrote.
From a therapeutic standpoint, targeting CACYBP—either alone or in combination with existing CDK or PI3K inhibitors—could offer new treatment strategies. The use of RNA interference (RNAi) technologies, such as shRNA or siRNA, is one avenue being explored to silence gene expression. Advances in lipid nanoparticle delivery systems may enhance the clinical application of these therapies.
Moreover, since both CACYBP and CDK1 are upregulated in LUAD and correlate with worse outcomes, they may serve as useful biomarkers for prognosis or treatment response.
Study Limitations and Future Directions
While the study offers significant insights, the authors acknowledge some limitations. The specific binding sites and detailed mechanism of interaction between CACYBP and CDK1 remain to be clarified. Additionally, the exact molecular crosstalk between CDK1 and the PI3K/AKT pathway in LUAD needs further investigation.
Nevertheless, the findings open up new research directions and strengthen the case for CACYBP as a promising target in lung cancer therapy.
Conclusion
The study by Wen et al. marks a significant step forward in understanding how LUAD progresses at the molecular level. By identifying the CACYBP–CDK1–PI3K/AKT axis as a promoter of tumor growth, the research offers valuable clues for developing targeted treatments and improving patient outcomes.
For researchers and clinicians alike, this work underscores the importance of exploring new molecular targets beyond traditional therapies—and opens the door to innovative strategies for combating LUAD.
The translation of the preceding English text in Chinese:
了解肺腺癌：一个沉默的杀手
肺癌仍是全球癌症相关死亡的主要原因。其中，非小细胞肺癌（NSCLC）约占所有肺癌病例的80–85%，而肺腺癌（LUAD）是最常见的亚型。肺腺癌尤其危险，因为其往往在无明显症状的情况下发展，使得早期发现十分困难。许多患者在确诊时已处于晚期，治疗选择有限，生存率较低。
尽管靶向治疗和免疫治疗的进展提高了部分LUAD患者的治疗效果，但仍面临诸多挑战。大量患者对免疫治疗无反应，而使用靶向药物的患者也常常出现耐药。因此，研究人员正积极寻找新的分子靶点，以更深入理解和对抗LUAD。
CACYBP在LUAD中的作用
近来受到关注的一个蛋白是钙环素结合蛋白（CACYBP）。CACYBP是一种多功能适配蛋白，参与蛋白降解、细胞周期调控和细胞骨架重建等多个细胞过程。此前研究显示，CACYBP在不同类型癌症中的作用不一——在某些癌症中（如肝癌、前列腺癌）促进肿瘤生长，而在其他类型（如乳腺癌、肾癌）中则起抑制作用。
尽管在其他癌症中的功能已较明确，CACYBP在LUAD中的具体作用仍不清楚——直到最近的一项研究揭示了答案。
新发现：CACYBP在LUAD中作为促瘤因子
在《Biomolecules and Biomedicine》发表的一项新研究中，来自南方医科大学及其他机构的研究人员探讨了CACYBP在LUAD中的表达及其生物学功能。通过分析癌症基因组图谱（TCGA）的RNA测序数据，研究团队发现LUAD肿瘤组织中CACYBP的表达明显高于正常肺组织。
进一步分析显示，CACYBP高表达与更晚的肿瘤分期及较差的总体生存率相关。免疫组织化学染色的临床样本也支持这一结果，显示LUAD组织中CACYBP蛋白水平升高。
实验验证CACYBP的致癌作用
为了研究CACYBP如何影响肿瘤行为，研究人员在LUAD细胞系（A549 和 NCI-H1299）中使用基因工具沉默该基因。结果显示，CACYBP表达下降抑制了细胞生长、迁移能力减弱，并诱导了细胞凋亡。这一发现无论在体外实验还是小鼠模型中都得到一致验证。
在小鼠体内实验中，CACYBP沉默细胞形成的肿瘤体积更小，且Ki-67（细胞增殖标志物）表达降低。以上结果共同证明，CACYBP促进LUAD进展，并可能成为一个治疗靶点。
关键机制揭示：CDK1的作用
在探索分子机制的过程中，研究人员发现细胞周期蛋白依赖性激酶1（CDK1）是CACYBP的关键下游靶点。CDK1在推动细胞周期进展和细胞分裂中扮演重要角色。
在对有无CACYBP表达的LUAD细胞进行RNA测序后，研究人员发现有1800多个基因表达存在差异。其中，CDK1因其在细胞增殖中的中心作用而被重点关注。免疫组织化学进一步证实，CDK1在LUAD组织中高表达，与CACYBP的表达趋势一致。共免疫沉淀（co-IP）实验显示CACYBP与CDK1直接相互作用，提示其之间存在直接的调控关系。
CDK1过表达逆转肿瘤抑制效应
为了进一步验证这一关系，研究人员在CACYBP被沉默的LUAD细胞中过表达CDK1。结果非常显著：CDK1的过表达恢复了被抑制的肿瘤特性，包括增强的细胞增殖、迁移能力以及减少的凋亡水平。
这一发现表明CDK1在介导CACYBP促瘤作用中发挥关键作用。
PI3K/AKT通路的参与
通路分析发现，当CACYBP被沉默时，PI3K/AKT信号通路明显受抑制。该通路在细胞存活、生长以及对癌症治疗的抵抗中具有重要作用。
为了确认CDK1与PI3K/AKT通路之间的联系，研究人员使用PI3K抑制剂（LY294002）处理LUAD细胞。结果显示，该处理逆转了CDK1带来的细胞增殖效应，证实CDK1部分通过该通路发挥作用。
对LUAD研究与治疗的启示
这项研究揭示了LUAD中一个此前尚未深入探索的机制——CACYBP–CDK1–PI3K/AKT轴是推动肿瘤发展的关键途径。
“这些发现支持了我们的假设，即CDK1至少部分通过PI3K/AKT通路参与LUAD细胞的致瘤潜能，”作者在文中写道。
从治疗角度看，靶向CACYBP，或与现有的CDK或PI3K抑制剂联合治疗，有望成为新的治疗策略。使用RNA干扰（RNAi）技术（如shRNA或siRNA）来沉默基因表达是一种正在探索的路径。脂质纳米粒技术的进展有望提高这些治疗策略的临床应用性。
此外，由于CACYBP和CDK1在LUAD中均表现为上调，并与不良预后相关，它们或可作为诊断或预测治疗反应的生物标志物。
研究局限与未来方向
尽管研究提供了重要见解，作者也指出一些局限性：CACYBP与CDK1之间的具体结合位点及其详细机制仍需进一步研究。同时，CDK1与PI3K/AKT通路在LUAD中的分子交叉机制仍不清晰。
尽管如此，本研究为LUAD的研究提供了新的方向，也强化了CACYBP作为肺癌治疗潜在靶点的价值。
结语
Wen等人的研究在揭示LUAD的分子机制方面迈出了重要一步。通过识别CACYBP–CDK1–PI3K/AKT通路作为肿瘤增长的推动因子，这项研究为开发靶向治疗和改善患者预后提供了有价值的线索。
对研究人员和临床医生而言，这项工作强调了探索传统治疗之外的新分子靶点的重要性，也为抗击LUAD打开了新的治疗思路。
Reference:
Ge Wen, Shaoqing Niu, Shiqi Mei, Senming Wang
Silencing CACYBP suppresses lung adenocarcinoma growth via CDK1 inhibition.
Biomol Biomed [Internet]. 2025 Mar. 19 [cited 2025 May 20];
Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/11849
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