Endometrial carcinoma (EC) is a leading malignancy of the female reproductive system, and postmenopausal women are most susceptible to this disease. Currently, the incidence and mortality of EC continue to increase, and an alarming number of young individuals are also being affected. Over the past three decades, EC incidence has risen by 132% [1]. According to the American Cancer Society, in 2023, the United States alone saw 66,200 new EC cases and 13,030 deaths, making EC the sixth leading cause of female cancer mortality [2]. Regrettably, the underlying mechanism governing EC progression remains unclear. Therefore, conducting comprehensive research in this area is crucial for optimizing treatment approaches and enhancing clinical outcomes for patients with EC.

Small GTPases, otherwise known as “Ras” (rat sarcoma), belong to a large family of hydrolases that modulate multiple cellular activities (cell differentiation, proliferation, and motility) by interacting with and hydrolyzing GTP to GDP [3]. The Ras superfamily has been classified into five major subfamilies based on sequence homology and physiological activities, namely, Ras, Rh, Rab, Ran, and Arf [[4], [5], [6]]. These proteins serve as strong signal modulators that regulate the progression of several human carcinomas [4,7]. As the most prominent members of the Ras subfamily, Rab proteins are small GTP-binding molecules that exhibit potent GTPase activity [8]. Rab35, a key member of the Rab GTPase family, resides in the plasma membrane and endosomes. Emerging evidence indicates that Rab35 regulates multiple cellular processes, including membrane trafficking, cell polarity, immunity, cytokinesis, phagocytosis, and cancer progression [9]. Several studies have documented that Rab35 regulates the migration and invasion of non-small-cell lung cancer [10], breast cancer [11], gastric cancer [12], and prostate cancer [13]. Nonetheless, the association of Rab35 with the migration and invasion of EC is yet to be elucidated.

Wnt signaling is categorized into noncanonical and canonical networks. The Wnt/β-catenin axis, commonly known as the canonical Wnt pathway, mediates signal transduction through the shuttling of β-catenin from the cytoplasm to the nucleus to activate target genes via TCF/LEF transcription factors. The Wnt/β-catenin axis is highly conserved, and signal dysregulation often results in serious diseases, including cancer and noncancerous conditions [14]. β-catenin functions as the key effector of the Wnt pathway and is strictly regulated by Wnt proteins and destruction complexes (including the adenomatous polyposis coli (APC) protein, Axin, glycogen synthase kinase 3β (GSK3β), and casein kinase I) [15]. In the presence of the stimulatory ligand Wnt, the Wnt ligand and surface proteins interact strongly to sequester the Axin–GSK3β–APC destruction complex, freeing β-catenin from degradation. Subsequently, the free β-catenin translocates to the nucleus and initiates the transcription of target genes [16].

Prior studies have asserted the intricate association between the nuclear translocation of β-catenin and the progression of triple-negative breast cancer [17], colorectal cancer [18], pancreatic cancer [19], glioma [20], prostate cancer [21], nasopharyngeal carcinoma [22], and other malignant tumors. One study observed dysregulation of the Wnt/β-catenin signaling in approximately 10%–45% of patients with EC [23]. Another study noted that S100P-mediated acceleration of β-catenin nuclear translocation effectively enhanced the proliferation of EC cells [24]. However, whether Rab35 promotes EC progression by activating the nuclear translocation of β-catenin is yet to be determined.

This study examined the significance of Rab35 in EC progression and its association with β-catenin nuclear translocation. This research aimed to validate Rab35 as a prognostic marker and therapeutic target for patients with EC.