LUAD is one of the most widely diagnosed subtypes of lung cancer. Owing to the unknown pathogenesis and unsatisfactory treatment effect, the mortality of LUAD patients remains high. In recent years, lncRNA has been applied as a potential tumor marker with promising research progress in LUAD.
In this study, both univariate and multivariate CPHR analyses were performed to establish a 5-lncRNA signature. This model showed high accuracy in both the “entire”and “primary datasets”. In contrast, our prognostic model outperformed the other prognostic features. Risk stratification analysis suggested that our prediction model applied to different subgroups. Finally, we employed GO and KEGG to detect the biological function of our predictive model. Our results seemingly explored how these 5 OS-related lncRNAs are involved in tumor progression. Finally, the lncRNA AL606489.1 showed a possible association with sex dimorphism.
Our prognostic model consisted of 5 LncRNAs, 4 (i.e., AC068228.1, SATB2-AS1, AC026355.1, AL606489.1) of which have been previously reported to be related to the prognosis of LUAD. For instance, SATB2-AS1 has been reported to promote tumor cell growth in osteosarcoma, and NSCLC. However, in colorectal cancer, SATB2-AS1 has the effect of inhibiting tumor cell metastasis. Similar to our result, AC026355.1 was reported to be an immune-related gene with tumor suppressor effects by Li et al. In past studies, AL606489.1 has been reported to be associated with autophagy, ferroptosis, and pyroptosis processes in LUAD tumor cells. LINC 01843 was first shown to be associated with LUAD progression. These reports provide a new direction for gene sequence studies in LUAD.
In the GO and KEGG analysis results, the mRNAs co-expressed with prognostic-associated lncRNAs were associated with processing and RNA transport in the nucleus, such as in the regulation of mRNA metabolic process and the regulation of RNA splicing. Past studies have demonstrated that one of the prognostic-related genes, SATB2-AS1, acts as a miR-299-3p sponge,promoted the development of NSCLC. The underlying mechanism is the promotion of tumor cell proliferation, cell cycle progression, and survival. Thus, the results of GO and KEGG seem to appropriately reflect the place of action that was associated with prognosis, lncRNA affects the prognostic effect in patients with LUAD.
In the risk stratification analysis, this predictive model showed a slightly better performance in male patients (P< 0.05) than in female patients (P = 0.08), which prompted us to further explore the reasons for this discrepancy.
In our study, AL606489.1 was highly expressed in men relative to that in women. Moreover, on the premise that there is no significant difference in the prognosis between men and women with LUAD, AL606489.1 exhibited high levels of prognostic association in male patients, while showing no significant (P = 0.05) prognostic association in female patients. Therefore, we suggest that AL606489.1 demonstrates a gender dimorphism in terms of the prognostic effects in patients with LUAD.
A person’s gender is one of the key factors affecting the occurrence and development of cancer throughout his or her lifetime. In addition to the sex-specificity of ovarian cancer in women and prostate cancer in men, several tumors are associated with a significant sex bias in terms of incidence, metastatic, prognosis, and therapeutic efficacy. As the attention to gender differences has increased, gender dimorphism has been mentioned in increasing studies.
In LUAD, sex bias is also associated with patients’ acquired behavior. For instance, Henschke et al. reported that women smoking was associated with a higher risk of lung cancer compared to men smoking among age-matched population.This difference may be attributable to the increased estrogen levels in women that promote lung cancer progression.Multiple studies have demonstrated that sexual dimorphism may be due to differences in the estrogen content between men and women, which develops into different prognostic effects between male and female patients with LUAD. LncRNA LINC00263 has been implicated as an oncogene in men and estrogen by Liu et al.However, the specific role of lncRNA in sex dimorphism has not been well studied. In the present case, AL606489.1 can hence be a breakthrough.
In our study, the action mechanism of AL606489.1 was explored by co-expression analyses. In the co-expression analysis, AL606489.1 was found to be highly correlated with the sarcolemmal membrane-associated protein (SLMAP) expression (correlation coefficient = 0.64) (Supplementary Table 3).A subform of the SLMAP has been reported to be a component of the microtubule (Mt) tissue center.Mts is an important therapeutic target for tumor cells. Clinically, some compounds that break Mt dynamics are also some of the most effective chemotherapeutics for cancer, such as vincristine alkaloids and taxanes.Similarly, the mt-targeted drugs (MTDs) form a major family of anticancer drugs with anti-mitotic and antiangiogenic properties that inhibit tumor progression, mainly by changing the Mt dynamics of the tumor and endothelial cells.However, there are no reliable markers that can be used for the prediction of the development of cancer sensitivity and resistance during treatment. In this study, AL606489.1 was found to be highly co-expressed with SLMAP and highly correlated with LUAD prognosis, indicating its potential as a reliable marker. Alternatively, the differential expression of AL606489.1 in men and women may be responsible for the clinical emergence of sex-differential efficacy of anticancer drugs that disrupt the Mt dynamics.
The limitations of the present study include the lack of external validation considering that the lncRNAs required in this study were inaccessible in the GEO database. Second, as RNA testing in the TCGA database is constantly updated, this study is slightly sample-limited. Finally, the preliminary conclusion that AL606489.1 demonstrates sexual dimorphism, as derived in this study, needs to be further validated through in vitro and in vivo biological experiments, if the external conditions support it.