Osteopontin Promotes Cell Migration and Invasion, and Inhibits Apoptosis and Autophagy in Colorectal Cancer by activating the p38 MAPK Signaling Pathway

Abstract

Background: Osteopontin (OPN) is highly expressed in colorectal cancer (CRC) and is associated with disease progression in vivo. High levels of OPN have been demonstrated to predict low survival rates in CRC. Autophagy is a process of self-digestion, which is thought to play a significant role in carcinogenesis. However, the mechanisms of OPN's effects on CRC cell autophagy have not been elucidated. Therefore, we aimed to investigate possible mechanisms of OPN's effects on CRC autophagy. Methods: HCT116 cell proliferation, apoptosis, and migration and invasion ability were identified by cell counting k¡t-8 assay, flow cytometry, wound healing assay, and transwell chamber invasion assay, respectively. The ratios of proteins LC3-II/LC3-I, P62, and Atg7 were analyzed by Western-blot. Expressions of Beclin-1, Atg4b, Bnip3, and Vps34, both in transcriptional and translational levels, were analyzed and compared by RT-PCR and Western blot. Immunofluorescence and co-focusing experiments were used to investigate the formation of autophagosomes. Results: The results showed that OPN can promote cell proliferation, migration, and invasion, as well as inhibit cell apoptosis. It was also demonstrated that OPN could inhibit cell autophagy. Further experiments revealed that the inhibitory effect of OPN on autophagy could be reversed by blocking the p38 MAPK pathway in HCT116 cells. Conclusion: OPN is involved in HCT116 cell progression and is capable of inhibiting cell autophagy possibly by activating the p38 MAPK signaling pathway, implying that OPN could be a potential novel molecular therapeutic biomarker in patients with CRC.

Mitogen-activated protein kinase signaling pathway in oral cancer (Review)

“…This function prevents cell apoptosis from being induced by various stimuli. Secondly, the pathway may indirectly suppress the activity of caspase-3 by activating the inhibitors of apoptosis molecules, including inhibitor of apoptosis and B cell lymphoma-2 family proteins (43,44). Thirdly, the pathway may block the release of mitochondrial cytochrome C and interfere with the activation process of upstream caspase-9, indirectly decreasing the activity of downstream caspase-3 (45).…”

Osteopontin contributes to effective neutrophil recruitment, IL‐1β production and apoptosis in Aspergillus fumigatus keratitis

“…However, apoptosis during infection can shape a suppressive, autoreactive or protective immune response . OPN seems to play an important physiological role in the efficient development of Th1 immune responses and cell survival by inhibiting apoptosis . These findings indicate that OPN knockdown may reduce inflammation by modulating neutrophil recruitment, decreasing proinflammatory cytokines and increasing apoptosis.…”

“…Although the role of OPN in mediating fungal keratitis is still not well understood, several studies indicate its role in antifungal immunity. For example, Inoue et al 19 found that OPN is essential in mediating the cluster formation of fungal receptors that detect Pneumocystis and plays a role as an adaptor molecule in the TLR2 and dectin-1 signaling pathways. Nishikaku et al 20,22 found that OPN is involved in granuloma formation and in the severity of P. brasiliensis infection.…”

“…It also functions as an adhesion protein involved in cell attachment and wound healing . In addition, OPN mediates cell activation and cytokine production, as well as promoting cell survival by regulating apoptosis . Furthermore, OPN is involved in granuloma formation and in modulating the severity of Paracoccidioides brasiliensis infection .…”

“…14,15 In addition, OPN mediates cell activation and cytokine production, as well as promoting cell survival by regulating apoptosis. [16][17][18][19] Furthermore, OPN is involved in granuloma formation and in modulating the severity of Paracoccidioides brasiliensis infection. 20 In vivo, OPN-deficient mice show increased susceptibility to low load, but not to high-load fungal infection.…”