Content area
Full text
Introduction
Cancer significantly impacts public health worldwide, with morbidity and mortality rates steadily increasing each year [1]. Despite the use of cancer immunotherapy to improve treatment outcomes in recent years, the 5-year survival rate remains unsatisfactory. A majority of patients exhibit limited responses to these therapies [2]. Therefore, there is an urgent requirement to identify predictive biomarkers for diagnosis and prognosis. Early assessment of patient benefit from these immunotherapy strategies is crucial. The application of cancer biomarkers has garnered considerable attention from researchers. Several studies have identified indicators associated with CIT response, including PD-L1 expression, tumor mutation burden (TMB), and eosinophilic count [3]. There is a need to explore novel cancer biomarkers to predict clinical outcomes and CIT responses.
The ADCYAP1 gene encodes adenylate cyclase-activating polypeptide (PACAP), a member of the secretin/glucagon/growth releasing hormone family. PACAP is widely distributed in both the central nervous system and peripheral organs [4]. It exists in two isoforms derived from the same precursor: PACAP-38, consisting of 38 amino acids, and PACAP-27, consisting of 27 amino acids [5]. PACAP is known to be involved in various biological processes [6]. Its diverse effects are mediated through binding to three G-protein-coupled receptors known as PAC1, VPAC1, and VPAC2 receptors. By binding to these receptors, PACAP can initiate various signaling pathways, including downstream adenylate cyclase (AC) or phospholipase-C (PLC) activation, as well as calcium-regulated mechanisms [4]. Thus, they are involved in neuronal death, inflammatory response, cellular fission and modulation of immune system [4, 7].
A substantial body of literature has demonstrated PACAP's involvement in various tumors, including testicular, lung, breast, prostate, colon, and pancreatic cancer, as well as neuroblastoma and glioblastoma [7]. The biological functions of PACAP exhibit controversy depending on the tumor phenotype and disease stage [7]. PACAP, in fact, has been shown to regulate other genes leading to the activation of tumor cell growth, survival, and hormone secretion [8]. Conversely, it is capable of impeding tumor cell progression through apoptosis by inhibiting their proliferation [9]. For instance, in glioblastoma, PACAP has demonstrated interference with the hypoxic microenvironment via modulation of hypoxia-inducible factors, achieved by inhibiting the PI3K/AKT and MAPK/ERK pathways [10]. A prior study has elucidated that PACAP stimulation prompts pro-apoptotic effects, increasing Bax expression and decreasing Bcl2 in MCF-7 breast...