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Ggct

Official Full Name
gamma-glutamylcyclotransferase
Background
The protein encoded by this gene catalyzes the formation of 5-oxoproline from gamma-glutamyl dipeptides, the penultimate step in glutathione catabolism, and may play a critical role in glutathione homeostasis. The encoded protein may also play a role in cell proliferation, and the expression of this gene is a potential marker for cancer. Pseudogenes of this gene are located on the long arm of chromosome 5 and the short arm of chromosomes 2 and 20. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.
Synonyms
GGCT; gamma-glutamylcyclotransferase; C7orf24, chromosome 7 open reading frame 24 , GCTG; CRF21; Ggc; MGC3077; cytochrome c-releasing factor 21; gamma -glutamyl cyclotransferase; GCTG; C7orf24; FLJ11717; C7orf24, CRF21, FLJ11717, GCTG, GGC, MGC3077, GGCT

Recent Research Progress

Chromosome 7 open reading frame 24 (C7orf24) was originally identified as a highly expressed protein in various types of cancer, and was later shown to γ-glutamylcyclotransferase (GGCT). GGCT depletion in cancer cells has an anti-proliferative effect in vitro and in vivo, and thus it is considered a promising candidate as a therapeutic target.

GGCT and CRC

Colorectal cancer (CRC) is one of the most common and deadly cancers in the world. CRC occurs due to the accumulation of genetic interactions and alterations. At present, the molecular research progress of CRC is still slow. It has been reported that there is a close relationship between GGCT expression and CRC cells. Recent studies have shown that GGCT silencing significantly inhibited cell proliferation and arrested cell cycle at the G0/G1 phase by regulating the expression of p21, p27 and cyclin E. Furthermore, GGCT silencing induced apoptosis in CRC cells by activating caspase-3 and cleaved poly-ADPribose polymerase pathways and down-regulating the phosphorylation proline-rich Akt substrate of 40 kDa (PRAS40) expression levels. These findings suggest that GGCT may be of critical importance in regulating cell proliferation and apoptosis in CRC and may be a useful diagnostic and therapeutic target for CRC.

GGCT and BC

Consumption of GGCT induces significant cellular senescence in various cancer cells. Knockout of GGCT in MCF7 breast cancer (BC) cells significantly up-regulated P21WAF1/CIP1, and the induction of cellular senescence and subsequent growth inhibition induced by GGCT depletion were dependent on p21WAF1/CIP1 up-regulation. GGCT depletion induced expression of p16INK4A, which regulated senescence induction in GGCT-silenced MDA-MB-231 BC cells. These results indicated that induction of cellular senescence mediated by up-regulation of cyclin-dependent kinase inhibitors is an important event in the anti-proliferative effect of GGCT depletion in BC cells, highlighting the potential of GGCT blockade as a therapeutic strategy to induce cellular senescence.

GGCT and Lung cancer

Lung cancer is rapidly developing as an invasive tumor and has become the leading cause of cancer-related death worldwide. It has been reported that GGCT knockdown can inhibit the proliferation and colony formation of lung cancer cells. Knockdown of GGCT arrested A549 lung cancer cells in the G0 / G1 phase, suggesting that GGCT knockdown inhibits G0 / G1-to-S phase transition to inhibit cell proliferation. Cyclin and cdks are two key regulatory molecules that determine cell cycle progression. Cyclin D1 binds to CDK4/6 to form an active complex of cyclin D1-CDK4/6, which phosphorylates retinoblastoma protein (pRb) and subsequently releases E2F transcription factor, leading to the activation of specific gene expression required for G0/G1-to-S phase progression. Furthermore, knockdown of GGCT reduced the expression of CDK4, CDK6 and cyclin D1, suggesting that GGCT knockdown may induce G0/G1 arrest potentially by disrupting the formation of the cyclin D1-CDK4/6 complex. In addition, an increase in cleavage of PARP was observed in GGCT knockdown cells, indicating induction of apoptosis. These results reveal a relationship between GGCT expression and lung cancer cell proliferation and can provide a suitable therapeutic target for lung cancer.

GGCT and Gastric cancer

Gastric cancer is one of the most common causes of cancer-related deaths worldwide, and is usually diagnosed late and misses the best treatment time. Therefore, early diagnosis and targeted therapy are critical to better predict gastric cancer. Recently, some studies have shown that the expression of GGCT in human gastric cancer tissues is higher than that in normal tissues. Knockdown of GGCT attenuates cell proliferation and colony forming ability of gastric cancer cells by increasing cell cycle arrest and inducing late apoptosis. These studies not only clarify the effects of GGCT depletion on gastric cancer, but also provide new evidence and basis for new methods for early diagnosis and targeted therapy of gastric cancer.

GGCT and ESCC

Esophageal cancer is the eighth most commonly diagnosed cancer in the world and the sixth leading cause of cancer death. Increased expression of GGCT has been reported to be common in invasive sophageal squamous cell carcinoma (ESCC) and high-grade intraepithelial neoplasia (HGIEN), but the frequency of observation in low-grade intraepithelial neoplasia (LGIEN) is much lower. GGCT expression was significantly associated with the presence and differentiation of lymph node metastasis. In the differential diagnosis of LGIEN and HGIEN, GGCT has high sensitivity and high specificity, while Ki-67 and p53 have only high sensitivity or high specificity. In addition, GGCT expression was higher in 7 of the 8 ESCC cell lines (KYSE series) than in the normal esophageal squamous cell line (Het-1A). The level of expression is strongly correlated with enzyme activity. These results indicate that overexpressed GGCT retains its enzymatic activity and can be a valuable biomarker for the diagnosis of HGIEN, which may develop into subepithelial invasion.

In summary, GGCT is up-regulated in several different types of cancer. Consequently, further studies of these organs with reference to relevant precancerous lesions are useful for clinical applications and for gaining insight into the mechanisms of carcinogenesis. Since this enzyme may have other functions than its role in the γ-glutamyl cycle, further detailed studies are needed to determine its exact role in tumor cells.

References:

  1. Dong, et al. Role of γ-glutamylcyclotransferase as a therapeutic target for colorectal cancer based on the lentivirus-mediated system. Anti-cancer Drugs, 2016, 27(10): 1011-1020.
  2. Matsumura, et al. Depletion of γ-glutamylcyclotransferase inhibits breast cancer cell growth via cellular senescence induction mediated by CDK inhibitor up-regulation. BMC Cancer, 2016, 16:748.
  3. Lin ZF, et al. γ-Glutamylcyclotransferase Knockdown Inhibits Growth of Lung Cancer Cells Through G0/G1 Phase Arrest. Cancer Biotherapy And Radiopharmaceuticals, 2015, 30(5): 211-216.
  4. Zhang et al. Knockdown of GGCT inhibits cell proliferation and induces late apoptosis in human gastric cancer. BMC Biochemistry, 2016, 17:19.
  5. Takemura k, et al. gamma-Glutamylcyclotransferase as a novel immunohistochemical biomarker for the malignancy of esophageal squamous tumors. Human Pathology, 2014, 45(2): 331-341.

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