The role of SHTN1 (salt-inducible kinase 3) in cancer has been relatively unexplored. This study demonstrates that SHTN1 expression is significantly elevated in bladder cancer and intensifies with advancing clinical stages. This suggests that SHTN1 contributes to the progression of bladder cancer by affecting cytochrome P450 drug metabolism and the EMT pathway.
Bladder cancer is a complex and multifactorial disease influenced by a mix of genetic, environmental, behavioral, lifestyle factors, including chemical exposures that elevate the risk of development. Specific chemicals and drugs, such as p-phenylenediamine, cyclophosphamide, praziquantel, and their metabolites [19]. A complex biological process is EMT, in which epithelial cells undergo a molecular or cytological transformation to become mesenchymal cells [20]. This transformation is crucial in the context of bladder cancer. As bladder cancer cells undergo EMT, they gain a heightened ability to migrate and infiltrate. This increased capacity enables them to penetrate the basement membrane and invade adjacent tissues. Such progression is a key factor in the spread and metastasis of bladder cancer, marking a critical phase in the disease's advancement [21].
Chemical exposure can impact various mechanisms such as cell adhesion, intercellular signaling pathways, autophagy, and gene expression regulation, triggering the initiation of EMT [22]. EMT not only remodels the surrounding stroma and alters the cytoskeleton but also is intricately linked to drug resistance in bladder cancer. Patients undergoing treatment may develop resistance to therapeutic drugs, a phenomenon closely associated with EMT, as evidenced by several studies [23]. Furthermore, the Cytochrome P450 enzyme family, vital in drug metabolism and clearance, particularly in the liver and other tissues, might interact with tumor development and EMT, especially during liver-based drug metabolism [24]. This interaction can lead to tumor cells developing resistance to conventional therapies, complicating treatment efforts [20]. Genes regulating EMT mechanisms present potential therapeutic targets for malignant urinary system tumors. In this context, In the fight against bladder cancer, photodynamic therapy has emerged as a highly targeted treatment option.
SHTN1 is notably upregulated in response to PDT, which may indicate its regulatory role and response mechanism to cellular stress and photo infection. However, it's important to note that tissue hypoxia is a prevalent characteristic in nearly all solid tumors. This hypoxic environment prominently influences the EMT, with lncRNAs, microRNAs, EIF5A2, Notch-4, and hypoxia itself being major regulators. Moreover, the epigenetic regulation of EMT is largely centered around hypoxia and TGF-β, emphasizing the complexity of cancer biology and the response to treatments like PDT [25]. It appears that lncRNAs, microRNAs, EIF5A2, Notch-4, and hypoxia are the primary regulators of EMTs. Importantly, the epigenetic regulation of EMT is profoundly influenced by hypoxia and TGF-β, highlighting their central roles in this critical cellular transformation [26]. In GSEA, SHTN1 demonstrated a significant up-regulation in response to hypoxia. This finding is particularly relevant in the context of PDT, which necessitates substantial oxygen consumption during the treatment process. Addressing the resultant hypoxia within tumors is crucial for enhancing the effectiveness of PDT [27]. Several studies have focused on overcoming hypoxia in tumor photodynamic therapy. These include employing micro/nano motors to enhance oxygen utilization within the tumor environment, using biosynthetic living organisms to supplement oxygen, and repairing tumor blood circulation to augment oxygen supply. Additionally, other innovative methods are being explored to address this challenge effectively [19, 28]. These innovative pathways have the potential to alleviate hypoxia-related issues in tumor treatment. Additionally, compounds like curcumin and its nanomedicine formulations, metformin, and Nitric Oxide have been effectively used to reduce oxygen consumption, thereby enhancing the efficiency of PDT. Given these advancements, it's recommended that PDT be integrated with other treatment modalities, such as radiotherapy and chemotherapy, to augment the overall therapeutic effectiveness against BLCA.
The microenvironment of BLCA is highly dynamic, comprising various cell types such as cancer cells, stem cells, and a range of immune cells, including neutrophils, macrophages, adipocytes, neurons, and neuroendocrine cells. These diverse cells interact and collectively influence the local tumor milieu. Crucially, the balance and functional activation of these immune cells are pivotal in determining tumor prognosis, and their activation is significantly influenced by the TME. Immune checkpoint inhibitors have emerged as a transformative therapy, enhancing treatment options and oncological outcomes for patients with urinary system cancers. In light of these insights, patients with high SHTN1 expression might exhibit a more favorable response to immunotherapy [29, 30].
While SHTN1 is identified as a key risk factor for bladder cancer, its role extends beyond this, significantly influencing the response to photodynamic therapy. This dual functionality of SHTN1 not only underscores its importance in disease progression but also highlights its potential as a therapeutic target in bladder cancer treatment. Further supporting its role, our analysis reveals that SHTN1 is associated with an immune environment conducive to treatment, reinforcing its relevance in BLCA therapeutic strategies.