Deciphering a common code: Unitary gene profile factor enabling Spontaneous Tumor Regression

ABSTRACT Spontaneous-remission of Cancer (SRC), well documented in humans, is the paradoxical process of natural permanent tumor elimination by host-tissue system without any toxicity, recurrence or cancer stem-cell formation. This rare biological phenomenon is usually associated with immune activation, apoptosis, tumor microenvironment as well as oncogenic suppression. Thus, to understand this strikingly complex event, it is utmost important to look into the genetic and molecular landscape in-depth. Majorly, cancer mortalities occur due to epithelial tumors, hence, to find out the contributing pathways involved we interrogated epithelial malignancies: Neuroblastoma (neural-crest tissue), and Melanoma (skin tissue). Neuroblastoma, the most prevalent tumor type in newborns, arises from embryonic nerve cells and have a very diverse clinical trajectory. Similarly, Melanoma another common skin tumor, developed from malignant transformation of melanocytes (cells producing melanin pigment). It is well-known that in numerous patients, both these malignant tumors spontaneously regress permanently, while in others, these tumors escalate to fatality. We investigated microarray expression of spontaneous regression of malignant neuroblastoma tumors (n=498), the patients having 4 temporal stages (S1-S2-S3-S4), and malignant melanoma tumors (n=22) having 4 time points (T1-T2-T3-T4) [i.e. total 520 patients, each 8 remission-route steps]. We studied differentially expressed genes (DEGs) common in both regressing Neuroblastoma and Melanoma, and analyzed the protein-protein interactions (PPI) as well as protein-miRNA networks. One crucial ubiquitous gene factor was found across each stage of both the regressing tumors. This focal gene codes for a spectrin-repeat protein which acts as a linker between nucleus-cytoskeleton, and aids in maintaining normal cell’s nuclear and cellular integrity (demarcated as a significant morphological change in tumor cells) by abetting the formation of Mut-S complex, which is a significant player in mis-match repair pathway. Strikingly, both this protein and miRNA were found to be commonly targeting PIK3CA protein through separate paths. We endeavor to unravel the mechanism of action and decipher the common gene factors across the entire tumor regression process in both Neuroblastoma and Melanoma. We meticulously identified the underlying biological pathways responsible for spontaneous regression. These results provide insights into the molecular genetics and underlying pathophysiology of SCR in Neuroblastoma and Melanoma, suggesting a role for precision therapeutics in the future that can help mimic this extraordinary prodigy by targeting the uniform factors mentioned in this study. Competing Interest Statement The authors have declared no competing interest.