Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 52 (12), 712-717

TOMM20 as a Potential Therapeutic Target of Colorectal Cancer

Affiliations

TOMM20 as a Potential Therapeutic Target of Colorectal Cancer

Sang-Hee Park et al. BMB Rep.

Abstract

Translocase of outer mitochondrial membrane 20 (TOMM20) plays an essential role as a receptor for proteins targeted to mitochondria. TOMM20 was shown to be overexpressed in various cancers. However, the oncological function and therapeutic potential for TOMM20 in cancer remains largely unexplored. The purpose of this study was to elucidate the underlying molecular mechanism of TOMM20's contribution to tumorigenesis and to explore the possibility of its therapeutic potential using colorectal cancer as a model. The results show that TOMM20 overexpression resulted in an increase in cell proliferation, migration, and invasion of colorectal cancer (CRC) cells, while siRNA-mediated inhibition of TOMM20 resulted in significant decreases in cell proliferation, migration, and invasion. TOMM20 expression directly impacted the mitochondrial function including ATP production and maintenance of membrane potential, which contributed to tumorigenic cellular activities including regulation of S phase cell cycle and apoptosis. TOMM20 was overexpressed in CRC compared to the normal tissues and increased expression of TOMM20 to be associated with malignant characteristics including a higher number of lymph nodes and perineural invasion in CRC. Notably, knockdown of TOMM20 in the xenograft mouse model resulted in a significant reduction of tumor growth. This is the first report demonstrating a relationship between TOMM20 and tumorigenesis in colorectal cancer and providing promising evidence for the potential for TOMM20 to serve as a new therapeutic target of colorectal cancer. [BMB Reports 2019; 52(12): 712-717].

Conflict of interest statement

CONFLICTS OF INTEREST

The authors have no conflicting interests.

Figures

Fig. 1
Fig. 1
TOMM20 overexpression resulted in the increased MitoATP production and promoted proliferation, migration, and invasion of CRC cells. (A, B) TOMM20 overexpressing cells showed increased proliferation rate compared to the vector transfected control cells as determined by the CCK-8 assay. (C) Cell cycle distribution by FACS analysis (D) Migration capacity determined by the wound healing assay. (E) Results of matrxigel invasion analysis (F) Cell proliferation in stable cell lines determined by the CCK-8 assay (G) Increase in ATP production by mitochondria -(H) Western blot analysis of total protein extracts showing increased amount of ATP5A. All quantitative results are expressed as mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001.
Fig. 2
Fig. 2
Reduced expression of TOMM20 diminished characteristics of cancer cells and caused mitochondrial dysfunction in CRC cells. (A, B) siTOMM20 transfection resulted in suppression of TOMM20 expression and stunted cell growth compared to the negative control cells. (C) Reduced migration of CRC cells by suppression of TOMM20 expression. (D) Reduction in invasion of siTOMM20 treated cells and corresponding expressions of E-cadherin and Vimentin. (E) Cell cycle analysis revealed the increased proportion of the S phase cells in siTOMM20 transfected cells. (F) BrdU incorporation experiment showed much increased BrdU-negative S phase cells (P1) in siTOMM20 transfected cells. (G) FACS analysis revealed increased apoptosis in siTOMM20 transfected cells. Western blot analysis revealed increased cleavage activities in siTOMM20 transfected cells. (H) FACS analysis using MitoTracker Green and Red staining showed increase in the number of mitochondria with lost membrane potential (P1). (I) Reduced ATP production in siTOMM20 treated cells. (J) MitoTracker Red staining for live cells and confocal microscopy showed mitochondrial fragmentation in siTOMM20-transfected cells. All quantitative results are expressed as mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001.
Fig. 3
Fig. 3
TOMM20 is overexpression in colorectal cancer tissues and Knockdown of TOMM20 suppressed CRC tumor growth in vivo. (A) Analyses of TOMM20 mRNA expression level in GEO data (***P < 0.001). (B) Relative expression of TOMM20 mRNA in 25 CRC patients as assessed by qRT-PCR analysis. The P-value was calculated by the Mann-Whitney test (*P < 0.05). Western blot analysis of TOMM20 was applied in 16 CRC tumor and matching normal tissues. (C) Representative Images of TOMM20 detected by IHC in CRC tissues and the non-tumor tissue. Scale bar = 200 μm. (D) Intratumoral injection of siTOMM20led to stunting of tumor growth (n = 5). (E) Tumor weight at 21 days after siRNA injection (F) TOMM20 and Ki67 expression characterized by immunohistochemical staining of xenografts tumors. Scale bar: 100 μm.

Similar articles

See all similar articles

References

    1. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67:7–30. doi: 10.3322/caac.21387. - DOI - PubMed
    1. Devetzi M, Kosmidou V, Vlassi M, et al. Death receptor 5 (DR5) and a 5-gene apoptotic biomarker panel with significant differential diagnostic potential in colorectal cancer. Sci Rep. 2016;6:36532. doi: 10.1038/srep36532. - DOI - PMC - PubMed
    1. Tsouma A, Aggeli C, Lembessis P, et al. Multiplex RT-PCR-based detections of CEA, CK20 and EGFR in colorectal cancer patients. World J Gastroenterol. 2010;16:5965–5974. - PMC - PubMed
    1. Sotgia F, Whitaker-Menezes D, Martinez-Outschoorn UE, et al. Mitochondrial metabolism in cancer metastasis: visualizing tumor cell mitochondria and the “reverse Warburg effect” in positive lymph node tissue. Cell Cycle. 2012;11:1445–1454. doi: 10.4161/cc.19841. - DOI - PMC - PubMed
    1. Birsoy K, Wang T, Chen WW, Freinkman E, Abu-Remaileh M, Sabatini DM. An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis. Cell. 2015;162:540–551. doi: 10.1016/j.cell.2015.07.016. - DOI - PMC - PubMed
Feedback