The Multifaceted Role of Striatin-interacting Protein 2 (STRIP2) in Disease Pathogenesis and Cancer Progression

Non-small Cell Lung Cancer

STRIP2 has emerged as a significant factor in the pathogenesis of non-small-cell lung cancer (NSCLC), particularly LUAD. Elevated STRIP2 expression in NSCLC tissues and cell lines correlates with poor clinicopathological features, such as advanced TNM stage, lymph node metastasis, and poor tumor differentiation. These associations suggest a possible oncogenic role of STRIP2 in NSCLC tumorigenesis (6, 13, 14). Moreover, Wang et al. provided evidence that support the diagnostic value of STRIP2 in distinguishing LUAD samples from normal lung tissue. STRIP2 was shown to be up-regulated in lung cancer and, moreover, its high expression levels were associated with poor LAUD prognosis. STRIP2 was also highly expressed in lung squamous cell carcinoma (LUSC) (6).

Mechanisms of STRIP2 in NSCLC: Proliferation, migration, and invasion. STRIP2 regulates key processes in NSCLC, including cell proliferation, migration, and invasion. It directly cooperates with insulin-like growth factor II mRNA-binding protein 3 (IGF2BP3), an mRNA-binding protein. Together, STRIP2 and IGF2BP3 stabilize the mRNA of transmembrane Bax inhibitor motif containing-6 (TMBIM6), an inhibitor of Bax-induced apoptosis, thereby promoting NSCLC progression. This stability is dependent on m6A modifications and STRIP2 enhances the m6A-positive content of TMBIM6, thereby increasing its mRNA stability. This interaction forms a positive-feedback loop. STRIP2 stimulates IGF2BP3 transcription, which in turn stabilizes TMBIM6 and contributes to tumorigenesis (11, 14). Additionally, STRIP2 plays a role in epigenetic regulation through P300/CBP-mediated acetylation of H3K27, underscoring its significance in NSCLC (14).

Akt/mTOR pathway. Qiu et al. found that STRIP2 expression was higher in LAUD cells than in normal lung cells and that STRIP2 expression is proportional to the expression of p-Akt and phosphorylated mammalian target of rapamycin (p-mTOR). These proteins are known to be involved in cell survival and proliferation (13). They highlighted a possible underlying pathway (Akt/mTOR) through which STRIP2 promotes cell proliferation and motility in LAUD (13).

Epithelial–mesenchymal transition. Qiu et al. reported that STRIP2 modulates epithelial–mesenchymal transition (EMT), a critical process in tumor migration and invasion. EMT markers, such as E-cadherin, N-cadherin, Vimentin, and MMP-9, are affected by STRIP2 expression levels, indicating their involvement in promoting EMT in LUAD cells (13). Suppression of the STRIP-2 gene significantly reduced the levels of EMT markers, and overexpression led to an increase in EMT markers by 2 folds for N-cadherin, Vimentin, and MMP-9; however, overexpression also led to a decline in E-cadherin (0.16 fold) (13).

Immune regulation. Zhang et al., emphasized that STRIP2 expression correlates with key immune checkpoint genes such as CD274, CTLA4, LAG3, and PDCD1LG2, highlighting its potential role in immune infiltration and tumor immunosuppression in LUAD (15). Lower levels of STRIP2 are associated with lower levels of these checkpoint genes, thus affecting tumor response to immune checkpoint inhibitors (15). A study by Wang et al. in 2022 showed that higher STRIP2 expression is associated with increased levels of certain immune cells (Th2 cells, NK CD56^dim cells, Tgd, Tem, and neutrophils) and decreased levels of others (macrophages, B cells, NK cells, dendritic cells, eosinophils, immature dendritic cells, T follicular helper cells, and mast cells) in LUAD (7). Moreover, Zhang et al. reported a positive correlation between STRIP2 and NK CD56^dim cells, Th2 cells, T gamma delta cells, T effector memory cells, and neutrophils; however, a negative correlation was found between STRIP2 and mast cells, T follicular helper cells, immature dendritic cells, dendritic cells, eosinophils, NK cells, and macrophages (15).

Therapeutic implications. Given the role of STRIP2 as an oncogene and its association with poor prognosis, targeting STRIP2 may have therapeutic potential in NSCLC. Inhibition of STRIP2 expression can significantly reduce tumor growth and metastasis, as demonstrated in animal models (14). Zhang et al. reported that STRIP2 interacts with insulin-like growth factor 2 mRNA-binding protein (IGF2BP), which can serve as prognostic and therapeutic biomarker for NSCLC. Moreover, targeting the P300/CBP-mediated H3K27ac activation pathway can reduce STRIP2 transcription, thereby mitigating its oncogenic effects (14). In LUAD, targeting STRIP2 may offer a strategy to modulate the tumor microenvironment and enhance the effectiveness of immunotherapy (7, 14, 15). Moreover, Wang et al. confirmed that STRIP2 can serve as a prognostic biomarker and its application may help in selecting the optimal therapy for patients with LAUD. They also reported resistance to immune checkpoint inhibitors accompanying high STRIP2 expression; thus, targeting STRIP2 may allow for a better response to immune checkpoint inhibition (7).

Breast Cancer

STRIP2 expression levels showed marked differences between disease-free and breast cancer patients, where STRIP2 was overexpressed in breast cancer patients. STRIP2 is closely related to the STRIPAK complex, which is the underlying mechanism by which STRIP2 affects breast cancer (7, 9, 12). Li et al. emphasized that STRIP2 overexpression was associated with a shorter overall survival (12).

Colorectal Cancer

Wang et al., reported that patients diagnosed with colorectal cancer (CRC) and had elevated levels of STRIP2, had reduced overall, disease-specific, and progression-free survival (7). Additionally, striatins in general were found to co-exist with adenomatous polyposis coli (12); however, there is a scarcity of detailed information regarding the role of the STRIP2 gene in colorectal cancer.

Prostate Cancer

Studies have demonstrated that STRIP2 plays a crucial role in prostate cancer cell migration. Bai et al. (16) reported that silencing STRIP2 in PC3 prostate cancer cells significantly reduces cell migration, indicating its importance in disease progression. Moreover, STRIP2 knockdown alters microtubule organization in PC3 cells, resulting in cell elongation, suggesting its involvement in cytoskeletal dynamics, which are critical for cancer cell motility (9, 11, 16). These findings underscore the potential of targeting STRIP2 to modulate prostate cancer cell behavior and develop novel therapeutic strategies.

Cellular Differentiation

Wagh et al. reported that STRIP2 knockdown led to the formation of a malformed heart and other abnormalities in the cardiovascular system. These abnormalities stemmed from the impaired expression of ventricular myosin heavy chain and cardiac myosin light chain. Moreover, they identified perinuclear and nucleolar products of the downstream STRIP2 gene. Additionally, they found that suppression of STRIP2 led to the elevation of pluripotency factors, and the cells remained undifferentiated, thus highlighting the crucial role of STRIP2 in cell differentiation (3). Similarly, Sabour et al. (2017) confirmed the presence of perinuclear and nucleolar bodies in undifferentiated embryonic stem cells, which were highly localized in the nuclei of differentiated cells (4). Moreover, Srinivasan and his colleagues reported that STRIP2 is an epigenetic regulator of pluripotency by modifying DNA KRAB-ZFPs and NuRD/TRIM28/HDACs/SETDB1 histone methyltransferase complex (5). It is well known that pluripotency increases neoplastic potential; however, its role in cellular differentiation needs to be further investigated to uncover the hidden pathways.

Angiogenesis

Suryavanshi et al. reported that STRIP2 interacts with CCM3, and STRIP2 or CCM3 knockdown in endothelial cells, increased stress fibers and reduced angiogenesis. Additionally, endothelial permeability increased upon STRIP2 knockdown (8).

Vascular Smooth Muscle Cells

Dai et al., and his colleagues reported that STRIP2 is involved in the proliferation and migration of vascular smooth muscle cells (VSMCs) and exerts this effect via the P38–AKT–MMP-2 signaling pathway, this highlights the importance of STRIP2 in atherosclerosis and might provide innovative approaches for prevention and treatment of atherosclerosis (11). Moreover, upon STRIP2 knockdown, the vascular endothelial growth factor levels increased remarkably. STRIP2 depletion has been linked to decreased levels of matrix metalloproteinases-2 and -9. They also reported that P38 mitogen activated protein kinase (MAPK) and protein kinase B (AKT), which are involved in cellular growth promotion and migration, were inactivated following STRIP2 silencing. In contrast, ERK1/2 and JNK were activated upon STRIP2 silencing; however, the role of STRIP2 in these two activated pathways has not yet been established, and future studies should address this point (11).

Cochlear Neuropathy

Pisciottano et al., 2019 that mice lacking STRIP2 displayed a decrease in neural response amplitudes and a reduction in the number of afferent synapses, indicating potential cochlear neuropathy (10). Moreover, within the inner ear, STRIP2 is highly expressed in outer hair cells (OHCs), inner hair cells (IHCs), and spiral ganglion. Additionally, STRIP2 expression was strong in the spiral ganglion but displayed a more diffuse pattern in the organ of Corti (10). The mechanism underlying the association between STRIP2 and inner ear function involves its interaction with the CaV1.3 L-type Ca²⁺ channels, which facilitates the proper assembly and maintenance of auditory nerve synapses. This interaction is important for proper auditory function, as evidenced by impaired auditory responses observed in mice lacking STRIP2 (10). This suggests that STRIP2 potentially plays a crucial role in inner ear physiology, particularly in the initial synapses between IHCs and afferent nerve fibers in the cochlea (10).

Cerebral Cavernous Malformations

Suryavanshi et al. highlighted an association between STRIP2 and endothelial cell physiology, particularly in the context of cerebral cavernous malformations (8). Patients with cerebral cavernous malformations, characterized by dilated leaky blood vessels, often exhibited loss-of-function mutations in CCM3, a component of the STRIPAK protein complex that includes STRIP2 among its constituents (8). The authors demonstrated that STRIP2 interacted with CCM3 and played a crucial role in endothelial cell function. The underlying mechanism involves regulation of stress fiber assembly through the Rho/ROCK signaling pathway. Depletion of STRIP2 leads to increased Rho/ROCK-mediated actomyosin contractility, resulting in enhanced stress fiber formation and altered endothelial junctions. The resultant cellular changes contribute to increased endothelial permeability and impaired angiogenesis, which are the hallmarks of cerebral cavernous malformations (8).

Heart Failure

Myoscape (myocardium-expressed, calcium channel-associated protein) is highly expressed in the human heart and localizes to sarcolemma at the t-tubule/z-disc interface, where it interacts and colocalizes with a-actinin 2 and the L-type Ca²⁺ channel (LTCC) (2). It is encoded by STRIP2 gene and plays a role in the regulation of cardiomyocyte calcium currents and cardiac contractility under both physiological and pathological conditions. Research has indicated that myoscape deficiency is associated with the loss of contractile function of cardiomyocytes, which leads to progressive heart failure (2,6). Furthermore, myoscape maintains LTCC surface expression by facilitating its interaction with LTCC and alpha-actinin at the t-tubule. Knockdown or ablation of myoscape in cardiomyocytes leads to reduced surface expression of LTCC and decreased calcium channel currents. This disruption of calcium cycling impairs contractility and contributes to the progression of heart failure. Given the crucial role of myoscape in heart contractility, strategies targeting its expression or activity may provide innovative therapeutic avenues for heart failure (2). Conversely, FAM40B knockdown in ESCs reduced cardiomyocyte differentiation, highlighting STRIP2’s role in cardiac development (3).