Hyaluronan‐Mediated Motility Receptor Potentiates Colorectal Carcinoma Progression Through PI3K/AKT/mTOR Pathway Modulation

ABSTRACT Objective This study aimed to interrogate the functional role of hyaluronan‐mediated motility receptor (HMMR) in modulating proliferative, migratory, and invasive phenotypes of colorectal cancer (CRC) cells, with an emphasis on its relationship with the PI3K/AKT/mTOR signaling cascade. Methods Protein expression levels of HMMR and components of the PI3K/AKT/mTOR pathway were comparatively analyzed in an exploratory paired tissue series of colorectal tumors and adjacent non‐neoplastic tissues ( n = 5) via Western blotting and immunohistochemistry. Functional perturbation was achieved through RNA interference and plasmid‐mediated overexpression of HMMR in HCT‐15 cells. Cellular behaviors were quantitatively assessed using Cell Counting Kit‐8 viability assays, flow cytometric analysis of cell cycle distribution, and motility/invasion assays. The functional involvement of the PI3K pathway was examined through fixed‐dose pharmacological modulation using an inhibitor and an agonist. Results HMMR expression was elevated in the paired CRC tissues relative to adjacent controls, accompanied by increased phosphorylation of PI3K/AKT/mTOR pathway components. Silencing of HMMR significantly reduced HCT‐15 cell viability over a 24–72 h interval ( p < 0.01), induced G1‐phase arrest ( p < 0.05), and attenuated migratory and invasive phenotypes ( p < 0.01), whereas ectopic HMMR expression produced the opposite pattern. Pharmacological pathway modulation attenuated or partially rescued HMMR‐associated phenotypes, supporting functional involvement of PI3K/AKT/mTOR signaling. Conclusion Within the experimental scope of this study, HMMR acts as a functional contributor to malignant phenotypes in HCT‐15 CRC cells and is associated with PI3K/AKT/mTOR pathway activation. These findings support a mechanistic relationship between HMMR expression and pathway activity without establishing a direct physical interaction between HMMR and individual pathway proteins.