IntroductionLung cancer shows the highest mortality rate and the second highest incidence globally among all tumor types1. According to its histopathological type, lung cancer can be divided into small-cell lung cancer and non-small-cell lung cancer (NSCLC). NSCLC accounts for approximately 85% of all lung cancer cases and is the main pathological type causing morbidity and mortality. To be specific, NSCLC can be further divided into lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), large-cell lung cancer, and other subtypes2. Of them, LUSC takes up around 25–30% of NSCLC cases and is the second most common subtype after LUAD3. The epidermal growth factor receptor (EGFR) is the most common clinical target in NSCLC, which shows the mutation rates of 30% in NSCLC and 50% in LUAD; however, in LUSC, the EGFR mutation rate is only 10%4. Other common genetic mutations, such as those of vascular endothelial growth factor and anaplastic lymphoma kinase, are also rare in squamous cell carcinoma. So far, no specific biomarker has been identified for the diagnosis and prognosis evaluation of LUSC, compared with other pathological types, and most LUSC patients are diagnosed at an advanced stage, accompanied by multiple complications5. Further, these patients have limited treatment options, and most of them have unfavorable prognosis. Therefore, it is particularly important to identify potential biomarkers for LUSC diagnosis and molecular subtyping, as well as therapeutic targets for LUSC treatment.In clinical practice, numerous LUSC patients exhibit sarcopenia in the course of their disease, and there is no available satisfactory explanation currently. Alpha-Sarcoglycan (SGCA), a member of the non-integrin family, not only forms part of the dystrophin-glycoprotein complex (DGC) that connects tissue cells with the extracellular matrix, but also has dual roles in signal transduction and structural integration6. The α-myoglycan protein, encoded by the SGCA gene, is usually engaged in protein-protein interactions through its independent transmembrane domain and cadherin-like domain7. Generally, SGCA, SGCB, SGCC, and SGCD co-encode the sarcoglycan complex, which forms a heterotetramer across the muscle membrane that connects the cytoskeleton and extracellular structure, thereby participating in the stabilization of the muscle membrane. Limb-girdle muscular dystrophy (LGMD) is the fourth most common inherited muscle disease, which has an incidence rate of about 1 in 20,000 individuals8. LGMD can be classified into LGMD type I and LGMD type II according to their genetic mode, with chromosome-recessive LGMD type II accounting for 90% of all cases9. The LGMD2D subtype of LGMD type II arises due to issues associated with the SGCA gene, which encodes the α-myoglycan protein. As one of the components of DGC, SGCA may be involved in the occurrence of sarcopenia. However, research on its role in oncology is still limited. And it remains to be further explored about whether SGCA expression is high or low in LUSC tissue, is the change of SGCA expression involved in the progression of LUSC, whether sarcopenia complicated with LUSC is related to SGCA, and is SGCA helpful for the diagnosis and prognosis of LUSC.Based on the above scientific hypotheses, in this study, we investigated SGCA expression, its related biological functions and clinical significance with tumor tissue samples and clinical data of patients through performing bioinformatics analysis as well as experiments using cells cultured in vitro and xenograft models in vivo. The findings demonstrate that low expression of SGCA promotes LUSC progression, and SGCA may be a promising biomarker for the diagnosis and prognosis evaluation of LUSC.Materials and methodsBioinformation analysis based on the cancer genome atlas (TCGA) dataThe RNA sequencing data and clinical characteristics of LUSC were sourced from TCGA database. Thereafter, the RNA matrix data were analyzed using R software 4.0.310. After excluding patients with incomplete clinical data, the data of 551 patients were included in this study.The gene expression data, comprising 551 patients downloaded from TCGA website, were categorized into two groups, including normal tissue (n = 49) and tumor tissue (n = 504) groups, following standard data preprocessing and analysis protocols. Based on the thresholds of statistical significance, |log2 fold change|>2 and p