Comprehensive analysis of KRT15 in pan-cancer and verification in lung adenocarcinoma

Introduction

As one of the most widespread malignancies globally, lung cancer has become the foremost cause of both fatalities and illness [1]. The early signs of lung cancer are relatively harmless, contributing to the challenge of detecting the disease at its initial stages [2], 3]. Advanced lung cancer is characterized by a high metastatic rate and an overall poor prognosis [4], [5], [6]. Lung cancer continues to have a high overall 5-year mortality rate, estimated at 78 % [7], 8]. Approximately 15 % of lung cancer cases are classified as small cell lung carcinoma (SCLC), with the remaining 85 % falling under non-small cell lung carcinoma (NSCLC) [9]. Within the category of NSCLC, there exist three subtypes: large cell carcinoma, lung squamous cell carcinoma (LUSC), and adenocarcinoma (LUAD) [10], [11], [12]. LUAD accounts for approximately 40 % of all lung cancers and is characterized as a malignant epithelial tumor with adenoid differentiation and/or mucous secretion [13]. Despite improvements in diagnosis and therapy in recent years, the overall survival (OS) outlook for individuals with LUAD remains suboptimal [13]. Currently, the complete pathogenesis of LUAD remains unclear. Consequently, the limited understanding of the fundamental processes involved in LUAD hinders the improvement of treatment outcomes. Thus, the paramount objective is to make significant progress in understanding tumor initiation and identifying novel biological markers to optimize prognosis.

Keratin is one of a family of structural fibrous proteins also known as scleroproteins. Ranging between 40 and 76 kDa, keratins (KRTs) are classified as structural proteins [2], 14]. As the primary building blocks of intermediate filaments (IFs) in the intracytoplasmic cytoskeleton of epithelial and endothelial cells, they play a major role in stress protection, cell integrity and structure, and protein targeting [15]. By anchoring into electron-dense desmosomal plaques and forming interconnections with other IFs, KRTs play a pivotal role in providing tensile strength to cellular components [15]. Due to their atypical expression patterns observed in different cancer types, KRTs serve as valuable biomarkers for discriminating between diagnoses and evaluating metastatic status [14]. In light of recent investigations, it is now evident that KRTs expressed in cancer cells possess a dual function; apart from their role as epithelial marker proteins, they act as mediators, engaging in interactions with diverse proteins to modulate signaling networks governing cell death [16], survival [9], proliferation [17], migration [18], invasion [18], and metastasis [19]. Chromosomally located at 17q21.2, keratin 15 (KRT15), commonly referred to as cytokeratin 15, is classified as one of the members in the KRT gene family [20]. KRT15 has been previously documented as a marker specific to skin stem cells within the hair follicle bulge [21], and it is known to have a vital function in regulating epidermal homeostasis [22]. A close link between KRT15 and tumorigenesis has also been demonstrated in recent research [23]. The upregulation of KRT15 was detected in squamous-cell carcinoma samples [24] and has been associated with an unfavorable prognosis in colorectal cancer [25]. Additionally, increased KRT15 expression is noted across various cancers including breast cancer [26], urothelial cell carcinomas [27], ameloblastoma [28], and hepatocellular carcinoma [29], while decreased expression is observed in oral squamous neoplasms [30], prostate tumors [31], and gastric cancer [32]. Further studies have linked KRT15 to breast cancer progression and its potential role as an independent prognostic factor [26], 33]. Additionally, differential expression in gastric cancer, associated with prognosis, was reported by Zhang et al. [32]. In addition, there is evidence to suggest that stem cells with KRT15-positive surface markers could become a source of specific cancer types under certain conditions [34]. Despite extensive research, the precise involvements of KRT15 in LUAD have remained largely unknown.

For the purpose of this study, we acquired RNA-sequencing (RNA-seq) data for LUAD and pertinent clinical patient data from TCGA and GEO databases to explore the potential prognostic value of KRT15. Utilizing these data, we conducted differential gene expression and functional enrichment analyses to pinpoint the genes and functional pathways exhibiting significant associations with KRT15 expression. Subsequently, a comprehensive analysis of tumor immune infiltration was conducted to investigate the potential correlation between KRT15 expression and the presence of immune cells. Furthermore, we conducted an assessment of the connection of KRT15 to clinicopathological and demographic parameters, followed by the analyses of survival and clinical subgroup prognosis, to ascertain the prognostic relevance of KRT15 in LUAD. Lastly, to strengthen the results, biological verification was carried out in vitro utilizing NCI-H1573 and PC-14 lung cancer cell lines. The findings from integrative bioinformatics and in vitro verifications suggest that KRT15 possesses the potential to be an innovative biomarker and therapeutic target, playing a role in predicting the prognosis and treatment response of LUAD patients.

Materials and methods

Results

Evaluation of the expression and prognosis of KRT15 in pan-cancer

Initially, to comprehensively study the expression pattern of KRT15 in various cancer types, we resorted to the TIMER2.0 software for data analysis, utilizing the TCGA database. Analysis of the data demonstrated a significant upregulation of KRT15 expression in UCEC, THCA, STAD, PCPG, PAAD, LUSC, LUAD, KIRP, KIRC, ESCA, COAD, CHOL, and CESC (Figure 1A and B). In contrast, BRCA, HNSC, KICH, and PRAD exhibited a down-regulated level of KRT15 expression (Figure 1A and B). Next, a comprehensive examination was undertaken to explore the plausible relationship between KRT15 expression and the OS rate across all 31 distinct cancer categories available in the TCGA repository. Based on the forest plots, a noteworthy correlation was observed between elevated KRT15 expression and unfavorable overall survival (OS) in BRCA, KIRC, PAAD, LUAD, and UCEC (Figure 1C). Furthermore, it was observed that heightened KRT15 expression correlated significantly with shorter PFS in CESC, KIRC, LGG, LUAD, LUSC, and PAAD (Figure 1D). Taken together, the findings presented above provide collective evidence of elevated KRT15 expression in numerous malignancies, indicating its plausible oncogenic function in these specific cancer contexts.

Figure 1:

Evaluation of the expression and prognosis of KRT15 in pan-cancer (A, B) representative plots depicting the expression of KRT15 in multiple cancer types from TCGA utilizing TIMER2.0 (A) and GEPIA (B). *, **, and *** represent the p-values less than 0.05, 0.01, and 0.001 respectively. The samples collected from healthy individuals were used as the normal controls. (C, D) representative forest plots representing the connections of KRT15 expression to OS (C) and PFS (D) in multiple cancer types from TCGA.

Evaluation of the connection between KRT15 expression and immune infiltration, immune checkpoint, TMB, and MSI status in pan-cancer

Initially, an investigation was conducted to explore the plausible association between KRT15 expression and the extent of immune infiltration across various types of cancers. In order to examine the connection between KRT15 expression and immune-infiltrating cells, the researcher employed the TIMER approach. A noteworthy association between KRT15 and infiltrating CD8⁺ T cells, CD4⁺ T cells, neutrophils, myeloid DCs, macrophages, and B cells was observed across multiple cancer types, including BLCA, COAD, ESCA, LUSC, MESO, READ, PRAD, STAD, TGCT, and THYM, as depicted by the data (Figure 2A). Following that, an investigation was carried out to examine the association between KRT15 expression and the expression levels of key immune checkpoints (TIGIT, SIGLEC15, PDCD1LG2, PDCD1, LAG3, HAVCR2, CTLA-4, and CD274) in pan-cancer. Based on the findings, a substantial association was evident between KRT15 expression level and one or more of these markers, except for UVM, READ, LAML, GBM, and BLCA (Figure 2B). Furthermore, an investigation was conducted to assess the correlation between KRT15 expression level and TMB. In PAAD, STAD, and READ, we identified a positive correlation between KRT15 expression level and TMB, whereas in PRAD, COAD, ESCA, and BRCA, a negative correlation was observed (Figure 2C). Lastly, a comprehensive analysis of the relationship between KRT15 expression level and MSI status was conducted, revealing a compelling positive link between KRT15 expression level and MSI status in TGCT, UCEC, LUSC, STAD, and SARC (Figure 2D).

Figure 2:

Evaluation of the connection between KRT15 expression and immune infiltration, immune checkpoint, TMB, and MSI status in pan-cancer (A, B) representative heat maps depicting the relationships of KRT15 expression with the infiltrated immune cells (A) and key molecules of immune checkpoints (B) in multiple cancer types. *, **, and *** represent the p-values less than 0.05, 0.01, and 0.001 respectively. (C, D) Representative forest plots showing the associations of KRT15 expression with the TMB (C) and MSI status (D) in multiple cancer types.

Evaluation of the connection between KRT15 expression to clinicopathological characters in LUAD

Next, a thorough examination was conducted to explore the connections of KRT15 expression to clinicopathological characters. A considerable upregulation of KRT15 expression levels was detected in LUAD samples in contrast to normal samples (Figure 3A). Additionally, in comparison to the normal samples, the expression of KRT15 was significantly upregulated in both male and female LUAD patients (Figure 3B), the LUAD patients with different races (Figure 3C), and the patients have different smoking histories (Figure 3D). However, no significant differences in KRT15 expression were observed between the patients with different genders (Figure 3B), races (Figure 3C), and smoking histories (Figure 3D). Furthermore, our findings also observed a substantial link of the KRT15 expression to the tumor stages (Figure 3E), tumor size (Figure 3F), node metastasis (Figure 3G), and distant metastasis (Figure 3H). A high level of KRT15 expression in LUAD patients represented a large tumor size (Figure 3F), high N metastasis (Figure 3G), and high distant metastasis (Figure 3H).

Figure 3:

Evaluation of the connection between KRT15 expression to clinicopathological characters in LUAD (A) demonstration of KRT15 expression levels is provided for LUAD tissues and matched normal tissues by a violin plot. (B, C) Representative violin plots showing the relationship of KRT15 expression in LUAD patients with different genders (B) or races (C). The samples collected from healthy individuals (tumor free) were used as the normal controls. (D) The connections of KRT15 expression to LUAD patients’ smoking history were shown. The LUAD patients without smoking were used as the normal controls. (E) Representative violin plot showing the expression KRT15 in LUAD patients with different stages. (F–H) Representative violin plots representing the correlations of KRT15 expression with the tumor size (F), node metastasis (G), and distant metastasis (H). **** represents the p-value less than 0.0001. The samples collected from healthy individuals (tumor free) were used as the normal controls.

Relationship of KRT15 expression level with prognostic in LUAD

The prognostic significance of KRT15 in patients with different cancers was explored first through an analysis of data extracted from the TCGA database. By adopting the median value of KRT15 as the dividing threshold, the cancer patients were allocated into high- and low-expression categories. The results indicated a significant relationship between raised KRT15 expression levels and unfavorable OS rates in patients with KIRC (Figure 4A), PAAD (Figure 4B), SKCM (Figure 4C), and THYM (Figure 4D), along with unfavorable PFS rates in patients with KIRC (Figure 4E) and PAAD (Figure 4F). Additionally, we also corroborated that the KRT15 expression exhibited an inverse correlation with both OS (Figure 4G–I) and PFS (Figure 4H) in lung cancer based on data from the GEO database, such as GSE30219 (Figure 4G and H) and GSE31210 (Figure 4I).

Figure 4:

Relationship of KRT15 expression level with prognostic in LUAD (A–D) representative KM plots showing the associations of KRT15 expression with the OS of patients with KIRC (A), PAAD (B), SKCM (C), and THYM (D). (E, F) Representative KM plots depicting the associations of KRT15 expression with the PFS of patients with KIRC (E) and PAAD (F). (G, H) The associations of KRT15 expression with the OS (G) and PFS (H) of lung cancer patients from GSE30219 database. (I) The associations of KRT15 expression with the OS (I) of lung cancer patients from GSE31210 database.

Single-cell analysis of KRT15 expression profile and the relationship with functional state in lung cancer

In light of the complex composition of tumor cells, single-cell transcriptome sequencing emerges as a vital tool for the comprehensive evaluation of diverse cancer cells, stromal cells, endothelial cells, and immune cells. Utilizing the TISCH website (http://tisch.comp-genomics.org/home/), the distribution of KRT15 expression in tumor cells was evaluated. Analysis of the GEO databases EMTAB6149 (Figure 5A–C), GSE117570 (Figure 5E–G), and GSE148071 (Figure 5I–K) demonstrated the predominant distribution of KRT15 expression in malignant cells, as opposed to its expression in immune cells, stromal cells, and other cell types. Meanwhile, obvious co-distribution of KRT15 expression with EGFR, a key molecular during the initiation, development, and progression of lung cancer, was also observed in EMTAB6149 (Figure 5C and D), GSE117570 (Figure 5G and H), and GSE148071 (Figure 5K and L) databases. Next, by accessing the CANCER SEA website (http://biocc.hrbmu.edu.cn/CancerSEA/), we validated KRT15 expression in single cells and investigated its relationship with the functional state of tumors. By evaluating data from GSE69405 (Figure 5M) and E-MTAB-6653 (Figure 5N-P), we observed a pronounced association between KRT15 expression levels and vital cellular processes, including the cell cycle, DNA damage, DNA repair, invasion, and DNA damage response.

Figure 5:

Analysis of KRT15 expression with single-cell sequencing data and its association with the functional state in LUAD (A) representative single cell plot showing the different cell types of lung cancer samples from GEO database EMTAB6149. (B, C) Representative violin plot (B) and single cell plot (C) depicting the distribution of KRT15 in different cell types of lung cancer samples from GEO database EMTAB6149. (D) The distribution of EGFR in the different cell types of lung cancer sample from GEO database EMTAB6149. (E) Representative single cell plot showing the different cell types of lung cancer samples from GEO database GSE117570. (F, G) Representative violin plot (F) and single cell plot (G) depicting the distribution of KRT15 in different cell types of lung cancer samples from GEO database GSE117570. (H) The distribution of EGFR in the different cell types of lung cancer sample from GEO database GSE117570. (I) Representative single cell plot showing the different cell types of lung cancer samples from GEO database GSE148071. (J, K) Representative violin plot (J) and single cell plot (K) depicting the distribution of KRT15 in different cell types of lung cancer samples from GEO database GSE148071. (L) The distribution of EGFR in the different cell types of lung cancer sample from GEO database GSE148071. (M−P) The relationships of KRT15 expression with indicated functional status in the lung cancer patients from GSE69405 (M) and E-MTAB-6653 (N–P) databases.

Evaluation of KRT15 expression in lung cancer tissue and cells

Utilizing the CCLE database, we detected a significant rise in KRT15 mRNA expression levels in LUAD cell lines (Figure 6A). Then, our analysis of the HPA database revealed elevated KRT15 protein expression levels in LUAD samples, with predominant distribution observed in the cytoplasmic and membranous regions (Figure 6B). Next, through the RT-qPCR assay, we ascertained elevated KRT15 mRNA expression levels in LUAD as compared to normal lung samples, supporting our findings (Figure 6C and D). Additionally, we also confirmed that LUAD samples exhibited dramatically elevated KRT15 expression at the translational level in comparison to the samples from health individuals (Figure 6E and F).

Figure 6:

Evaluation of KRT15 expression in lung cancer tissue and cells (A) representative forest plot showing the transcription of KRT15 in different LUAD cell lines obtained from CCLE analysis. (B) The protein of KRT15 at the translation level was analyzed by IHC method using The human protein atlas database. (C, D) Representative bar graph (C) and estimation plot (D) depicting the transcription of KRT15 between tumor and non-cancer tissues from LUAD patients. The adjacent noncancerous tissues were used as the normal controls. (E, F) Representative blot (E) and bar graph (F) representing the translation of KRT15 between tumor and non-cancer tissues from LUAD patients. The adjacent noncancerous tissues were used as the normal controls. ** and **** represent p-values less than 0.01 or 0.0001 respectively.

Silencing of KRT15 suppresses the growth, metastasis, and survival of lung cancer cells

The results obtained above indicate the potential involvement of KRT15 in cell proliferation, metastasis, and cell survival. To further elucidate the functional significance of KRT15 in lung cancer cells, a series of biological function assays were carried out. As shown in Figure 7A, a targeted siRNA directed against the KRT15 sequence led to a significant decrease in KRT15 expression in both NCI-H1573 and PC-14 cells (Figure 7A). The CCK-8 assay demonstrated significant suppression of the growth in NCI-H1573 (Figure 7B) and PC-14 (Figure 7C) cells upon down-modulation of KRT15 (Figure 7B and C). Additionally, inhibition of KRT15 resulted in a significant decrease in migrative (Figure 7D and E) and invasive (Figure 7F and G) capacities of NCI-H1573 (Figure 7D–F) and PC-14 (Figure 7E–G) cells, as evidenced by the transwell assay (Figure 7D–G). Finally, the apoptotic status of NCI-H1573 and PC-14 cells after KRT15 silencing was monitored and the results demonstrated that, in comparison to the control NCI-H1573 and PC-14 cells (siNC), those KRT15-deficient NCI-H1573 (Figure 7H) and PC-14 (Figure 7I) cells exhibited dramatically increased cell apoptosis, suggesting the promotion of KRT15 in the survival of lung cancer cells.

Figure 7:

Silencing of KRT15 suppresses the growth, metastasis, and survival of lung cancer cells (A) representative bar graph showing the transcription of KRT15 in human NCI-H1573 and PC-14 lung cancer cells after indicated treatments. (B, C) The growth of human NCI-H1573 (B) and PC-14 (C) lung cancer cells with or without KRT15 deficiency was monitored by CCK-8 method. (D–G) Representative images (up panels) and bar graphs (low panels) representing the migration (D, E) and invasion (F, G) of human NCI-H1573 (D, F) and PC-14 (E, G) lung cancer cells with or without KRT15 silencing. (H, I) Representative histograms (left panel) and bar graphs (right panel) depicting the apoptotic rates of human NCI-H1573 (H) and PC-14 (I) lung cancer cells with or without KRT15 silencing. *, **, and *** represent the p-values less than 0.05, 0.01, and 0.001 respectively. The cells transfected with the siRNA-control (siNC) plasmids were used as the controls.

Discussion

The convergence of rapid medical technological advancements and the tireless dedication of oncologists in research have led to a more scientific, universally applicable, and personalized approach in the diagnosis, monitoring, and treatment of oncological conditions. As a type I keratin, KRT15 exhibits significant expression in the basal layer and stratified epidermis of human skin [37]. Dysregulated expression of KRT15 is observed in individuals diagnosed with a range of cancer types, such as breast invasive carcinoma [20], colorectal cancer [25], renal cell carcinoma [23], and endometrial cancer [38]. According to a previous investigation, KRT15 exhibits upregulation specifically in a subgroup of invasive ureteric and urinary bladder cancers [27]. Additionally, the presence of lymphovascular invasion and higher International Federation of Gynecology and Obstetrics (FIGO) stage in endometrial cancer patients is significantly associated with the KRT15 protein, while KRT15 mRNA exhibits correlation solely with unfavorable FIGO stage [27]. Furthermore, in patients afflicted with esophageal carcinoma, KRT15 is linked to the advanced T stage and TNM stage, along with the occurrence of lymph node metastasis [39]. However, no research has been conducted to explore the clinical role and regulatory mechanism of KRT15 in lung cancer patients.

This pioneering research presents the first comprehensive exploration of KRT15 in pan-cancer, offering a novel and in-depth perspective. Among the most prevalent malignancies worldwide, NSCLC is prominent, with LUAD contributing to 40 % of all NSCLC cases. Based on our analysis, a significant relationship between KRT15 expression levels and the OS and PFS of LUAD patients was observed. This prompted us to undertake a meticulous investigation to further elucidate the intricate biological function of KRT15 in the context of LUAD. Our study aimed to unravel the crucial involvement of the KRT15 gene in the advancement of various malignancies. In order to fulfill our aim, we conducted an exhaustive search of data encompassing a broad range of cancer types and included a substantial number of participants. In the preliminary stage, we observed the disrupted expression of KRT15 in a range of malignancies. Through the implementation of the Cox regression model, we discerned unique associations between KRT15 expression and varied survival markers, suggesting its potential as a promising prognostic component in specific cancers.

Immunotherapy is currently a highly favored and extensively discussed topic in the field of oncology. The presence of tumor-infiltrating lymphocytes, the assessment of TMB, and the evaluation of MSI status are pivotal factors influencing the response to immunotherapy and dictating the clinical outcomes in cancer [40]. According to our investigation, KRT15 consistently elicited activation in all six diverse immune cell types (neutrophils, CD8+ T cells, macrophages, dendritic cells, CD4+ T cells, and B cells) across the majority of cancer types. Across approximately 20 types of cancers, a significant association was observed between the key immune checkpoints (CD274, CTLA-4, HAVCR2, LAG3, PDCD1, PDCD1LG2, SIGLEC15, and TIGIT) and KRT15 expression, excluding UVM, READ, LAML, GBM, and BLCA. The identification of particular gene mutations may enable the anticipation of patients’ prognoses and treatment outcomes. Increased somatic TMB and MSI have demonstrated a positive correlation with enhanced efficacy of immunotherapy and favorable OS across various cancer histology. Mutations in mismatch repair genes and the compromised function of these genes were identified as the underlying factors contributing to MSI. Herein, we identified a positive correlation between KRT15 expression level and TMB in PAAD, STAD, and READ, whereas a negative correlation in PRAD, COAD, ESCA, and BRCA. These comprehensive findings suggest the potential role of KRT15 in promoting tumor growth by upregulating MSI and TMB via the modulation of genes associated with mismatch repair. Tumors harboring high TMB and MSI-H status are characterized by prominent immune cell infiltration, making them more amenable to potential immune checkpoint inhibitor responses [41], [42], [43]. In view of this understanding, these high KRT15-expressed cancer types could offer potential advantages for immune checkpoint inhibitor treatments. The use of single-cell transcriptome sequencing and KEGG pathway analysis highlighted a noteworthy connection between KRT15 expression and cell proliferation in NSCLC. Functional assays further affirmed the inhibitory impact of KRT15-deficiency on lung cancer cell growth and its influence on cell growth.

According to a previous study, in colorectal cancer cells, KRT15 exerts regulatory control over the β-catenin/matrix metalloproteinase-7 (MMP-7) pathway, thereby facilitating the migration and invasion [44]. Additionally, a connection of KRT15 expression with cell apoptosis was also observed [38]. In line with these publications, our results also demonstrated that KRT15 expression is closely connected to metastasis and survival, silencing of KRT15 could dramatically suppress the migration, invasion, as well as survival of lung cancer cells.

Additionally, in our study, we employed three major datasets, The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and the Human Protein Atlas (HPA), to comprehensively investigate the clinical relevance of the KRT15 gene across a diverse array of cancer, with a focused analysis on LUAD. Each dataset was chosen for its unique strengths and contributions to cancer research. TCGA provided a robust foundation with its comprehensive genomic and transcriptomic profiles, enabling us to perform a detailed pan-cancer analysis and identify KRT15’s roles across various cancer types. GEO supplemented our findings by offering additional genomic datasets, which allowed us to validate the functional implications of KRT15 in cancer-specific signaling pathways and tumor behaviors. The HPA was instrumental in corroborating protein expression profiles, linking genetic alterations observed in TCGA and GEO with protein-level evidence, thereby strengthening our hypothesis about KRT15’s involvement in tumor progression.

To ensure the consistency and compatibility of our results across these datasets, we applied rigorous data preprocessing and normalization techniques. This approach mitigated technical variances and aligned the data for comparative analysis. Notably, the consistency of our findings across these distinct datasets was reinforced through cross-validation techniques, where key results related to KRT15’s role as a biomarker and potential therapeutic target were robustly supported. These efforts ensured that our study’s conclusions were based on reliable and reproducible evidence, thus enhancing the overall credibility of our findings regarding the significance of KRT15 in cancer prognosis and therapy.

In this study, while we demonstrated the potential role of KRT15 as a biomarker and therapeutic target across a diverse spectrum of cancers, we acknowledge several limitations. The heterogeneity of cancer types included in our pan-cancer analysis, although valuable for broad biomarker discovery, introduces variability that may affect the generalizability of our findings to individual cancer types. Each cancer type possesses unique genetic, epigenetic, and microenvironmental characteristics that could influence the expression and functional impacts of KRT15. Consequently, the translational relevance of our results may be constrained by this diversity. Furthermore, our reliance on in vitro models for validating the functions of KRT15, while essential for initial mechanistic explorations, may not fully capture the complex interactions and behaviors present within the in vivo tumor milieu. Such models lack the comprehensive representation of immune system interactions and the tumor microenvironment, which are crucial for assessing the therapeutic potential of targets like KRT15. Future investigations employing in vivo models and patient-derived samples will be critical to overcome these limitations and enhance the clinical applicability of our findings.

In conclusion, our study is the inaugural endeavor to undertake a thorough analysis of KRT15 in pan-cancer. Our research unveiled an elevation in KRT15 expression across various malignancies, demonstrating an adverse correlation with OS. Our validation experiment demonstrated a considerable increase in KRT15 expression in LUAD samples when compared to the corresponding non-tumor samples. The implications of this finding highlight KRT15 as a potential biological marker for LUAD. Furthermore, its involvement in LUAD advancement is closely linked to its role in promoting cell growth, metastasis, and survival of LUAD cells.