TMEM206 promotes the malignancy of colorectal cancer cells by interacting with AKT and extracellular signal-regulated kinase signaling pathways.

BACKGROUND

The roles of TMEM206, a new transmembrane protein, in cancer, including colorectal cancer (CRC), are unknown. Related family members, including TMEM16A, TMEM132A, and TMEM176B, have been shown to be involved in various biological behaviors. In addition, TMEM88 has been reported to promote non-small-cell lung cancer. In this study, we examined the roles of TMEM206 in CRC.

METHOD

Real-time reverse transcription polymerase chain reaction was used to measure TMEM206 messenger RNA (mRNA) levels in clinical specimens and transfected cell lines. Immunohistochemistry was used to determine the relationship between TMEM206 expression levels and clinical data. Plasmids and small interfering RNA were used to upregulate and silence TMEM206, respectively. Protein expression levels and signaling pathway modulation were validated through western blot analysis. Colony formation, MTT, cell migration and invasion assays, and flow cytometry analyses were used to test the potential roles of TMEM206 in CRC. Co-immunoprecipitation was used to evaluate the interaction between TMEM206 and AKT.

RESULTS

Investigation of the clinical significance of TMEM206 expression in CRC tissues revealed that TMEM206 mRNA and protein levels were higher in CRC tissues than in paired normal adjacent tissues (p < 0.05). TMEM206 overexpression was positively associated with T stage of cancer and UICC stage ( p < 0.05) and negatively related to differentiation of CRC ( p = 0.015). Upregulation or silencing of TMEM206 promoted or inhibited the proliferation of CRC cells and positively or negatively regulated the levels of phospho-AKT and downstream signaling pathway components (phospho-glycogen synthase kinase 3β and cyclin D1), respectively. Moreover, silencing of TMEM206 in cell lines arrested CRC cells in the G1 stage of the cell-cycle. In addition, upregulating or silencing TMEM206 increased or decreased cell invasion and migration in vitro and positively or negatively altered levels of the phospho-extracellular signal-regulated kinase (ERK) and phospho-focal adhesion kinase 397, respectively. Co-immunoprecipitation demonstrated that AKT and TMEM206 proteins interacted. Furthermore, TMEM206 promoted the development and progression of CRC by enhancing the interactions between the AKT and ERK signaling pathways.

CONCLUSION

TMEM206 controlled the progression of CRC by accelerating CRC cell proliferation and promoting CRC cell migration and invasion. The target of TMEM206 may be AKT, which is known to be involved in modulating the biological behaviors of various cancers.