In our study, we identified shared genes between laryngeal cancer and lung cancer, namely UBE2C, POLQ, RAD51, HOXB7, EDNRB, GPD1L, F10, SORBS2, and CXCL12. These genes exhibit high accuracy in diagnosing both types of cancer, providing valuable insights for clinicians in diagnosing, preventing, or treating second primary lung cancer in laryngeal cancer patients. Furthermore, our findings indicate that mutations in these genes increase the susceptibility of laryngeal cancer patients to primary cancer or local recurrence, while also worsening the prognosis of lung cancer patients. This sheds light on why laryngeal cancer patients are more prone to developing second primary lung cancer and underscores the poorer prognosis for patients with both cancers compared to those with pure laryngeal cancer. The relationship between laryngeal cancer and the development of second primary lung cancer is complex, involving multiple transcription factors and miRNAs that primarily act during the cell cycle. Additionally, our study highlights the pivotal role of CXCL12 in tumor microbiota, particularly in inositol phosphate metabolism. The similarity in cell populations between lung cancer and laryngeal cancer, due to their shared respiratory tract, may contribute to the development of both cancers. Furthermore, the influence of cell population on metabolism promotes the initiation and progression of laryngeal cancer and lung cancer. Lastly, our findings reveal striking similarities in immune cell infiltration, with macrophages playing a significant role in tumorigenesis and development.
Previous studies have demonstrated that UBE2C regulates cell cycle progression and autophagy through the UBE2C/CDH1/DEPTOR axis in lung cancer, promoting tumor cell progression23. Genes such as POLQ and RAD51 play a crucial role in DNA damage repair, which can be both beneficial and detrimental. Deletion or inhibition of these genes can lead to tumor cell formation24–26. Additionally, these genes can serve as diagnostic predictors of tumors, aligning with previous literature 27,28. Tumor formation occurs due to various factors, including mutations in genes (deletions, missenses, etc.) during the DNA replication process, coordinated action of multiple transcription factors and miRNAs. Previous research has indicated that has-miR-193b-3p negatively regulates the expression of cyclin D1, thereby regulating the proliferation of meningioma cells29. Our study found that the mutated group of laryngeal cancer patients had a higher likelihood of developing primary cancer and local recurrence compared to the non-mutated group. Therefore, we speculate that the higher occurrence of second primary lung cancer in laryngeal cancer patients is due to gene mutations shared between the two cancers, as they both affect the respiratory tract, which is frequently exposed to airway-related factors. Previous studies have identified smoking, alcohol consumption, and radiation therapy as risk factors for the development of second primary lung cancer in laryngeal cancer patients. Both smoking and radiation therapy can induce gene mutations, supporting our hypothesis12,30.
Bacterial lipopolysaccharide (LPS) is a crucial component of the bacterial cell wall and exhibits high bioactivity. LPS functions as a protective barrier for bacteria, enabling them to evade immune recognition through modifications in groups31. Previous studies have reported that LPS increases lactate levels in both mouse models and human cells32,33. Additionally, LPS-induced changes in histone lysine expression of LINC00152 have been found to promote the occurrence and development of tumors34. Another study by Nan Li et al. discovered that LPS promotes the expression of CXCR7, leading to the proliferation and metastasis of gastric cancer35. CXCR7 serves as the secondary receptor for CXC12. Consequently, we aimed to investigate the role of bacterial lipopolysaccharides in laryngeal and lung cancers. Our study revealed a close association between CXC12 and bacterial lipopolysaccharides, with CXCL12 primarily mediating inositol phosphate metabolism. Notably, inositol phosphate metabolism significantly influences the occurrence and progression of breast cancer36. However, the relationship between laryngeal cancer and second primary lung cancer remains unknown.
Single-cell sequencing technology has been widely utilized in various aspects of cancer research, such as determining tumor heterogeneity, identifying cellular properties, discovering novel biomarkers, and investigating molecular and functional strategies37,38. In our study, we employed single-cell sequencing technology to identify relevant cell populations in laryngeal and lung cancer tissues. We found that B cells, Basophils, CD4 + T cells, CD8 + T cells, Dendritic cells, Monocytes, Neutrophils, NK cells, Progenitors, and T cells were active in laryngeal cancer. On the other hand, the main cell populations in lung cancer were Intermediate monocytes, Classical monocytes, Terminal effector CD8 T cells, Th1 cells, Non-switched memory B cells, Natural killer cells, and BM. Both types of cancer were primarily characterized by immune cell components. Furthermore, we explored the impact of these cell populations on tissue metabolism and discovered that Intermediate monocytes regulate Inositol phosphate metabolism. These monocytes not only play a crucial role in promoting angiogenesis but also contribute significantly to cancer development 39,40. In the context of cancer, monocyte subsets exhibit various functions that can either promote or fight tumor immunity. These functions include phagocytosis, secretion of tumoricidal mediators, promotion of angiogenesis, remodeling of the extracellular matrix, recruitment of lymphocytes, and differentiation into tumor-associated macrophages and dendritic cells41–44. Reham Hammad et al. observed that the upregulation of intermediate monocyte frequency and the expression of hsa-miR-21-5p served as sensitive indicators of progression from cirrhosis to hepatocellular carcinoma (HCC)45. Based on our hypothesis, we propose that after the development of laryngeal cancer, the cell population in the lungs becomes relatively active due to the shared respiratory tract. This activation of Intermediate monocytes triggers inositol phosphate metabolism and promotes tumor formation and development.
Previous studies have demonstrated the crucial role of macrophages in the tumor microenvironment (TME), influencing various processes such as angiogenesis, extracellular matrix transformation, cancer cell proliferation, metastasis, immunosuppression, and resistance to chemotherapy and checkpoint blockade immunotherapy 46,47. Macrophages exist in an undifferentiated state known as M0 and can be polarized into M1 or M2 cell types based on specific signals and the microenvironment. In the initial stages of tumor formation, M1 macrophages within the TME trigger inflammatory and anti-tumor responses. These M1 macrophages can be induced by cytokines like IFN-γ and TNF-α, or by recognizing bacterial lipopolysaccharide (LPS)47,48. On the other hand, M2 macrophages are induced by Th2 cytokines (IL-4, IL-13, etc.) and exhibit anti-inflammatory and immunomodulatory effects by producing anti-inflammatory factors, thus promoting tumor cell growth49,50. In the context of laryngeal cancer patients, it is conceivable that macrophages play a role in anti-cancer and other immune regulatory processes, while M2 macrophages contribute to cancer development in lung tissue through anti-inflammatory and metabolic pathways.
In our project, we made a novel discovery regarding the shared genes between laryngeal cancer and second primary lung cancer. We also investigated the interaction between transcription factors and miRNAs, which play a role in promoting the formation of secondary primary lung cancer. This process is regulated by macrophages and intratumoral cell populations. Our findings provide valuable insights for the diagnosis and treatment of laryngeal cancer. However, it is important to acknowledge the limitations of our research, including the lack of experimental and clinical data to validate our hypothesis. Future studies should aim to address this gap and further supplement the topic with sufficient experimental verification.