LASS2

Official Full Name

ceramide synthase 2

Organism

Homo sapiens

GeneID

29956

Background

This gene encodes a protein that has sequence similarity to yeast longevity assurance gene 1. Mutation or overexpression of the related gene in yeast has been shown to alter yeast lifespan. The human protein may play a role in the regulation of cell growth. Alternatively spliced transcript variants encoding the same protein have been described. [provided by RefSeq, Jul 2008]

Synonyms

CERS2; L3; LASS2; SP260; TMSG1;

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Detailed Information

Recent Progress

Homo sapiens longevity assurance homolog 2 of yeast LAG1 (LASS2), also known as tumor metastasis suppressor gene 1 (TMSG1), was firstly cloned in 1999. However, its antitumor molecular mechanisms remain to be elucidated. LASS2/TMSG-1 could directly interact with the C subunit of Vacuolar H+ ATPase (V-ATPase), which suggested that LASS2/TMSG1 might inhibit the invasion and metastasis through regulating the function of V-ATPase (Fig.1). Results of a study aiming to provide molecular mechanism of the interaction between LASS2/TMSG1 and V-ATPase showed that there were no obvious differences of V-ATPase expression among different transfected cells and the control. However, V-ATPase activity and intracellular pH was significantly higher in the variant transfectants with Homeodomain of LASS2/TMSG1 than that in the control. It was demonstrated that there is a direct interaction of Homeodomain of LASS2/TMSG1 and ATP6V0C. Loss of Homeodomain markedly enhanced the proliferation ability but weakened the apoptotic effect of LASS2/TMSG1. This means that LASS2/TMSG1 could regulate V-ATPase activity and intracellular pH through the direct interaction of its Homeodomain and the C subunit of V-ATPase. Their interaction could play important roles in the apoptosis of tumor cells.

Fig. 1. The V-ATPase pathway. (Calorie et al, 2001)

In one study, researchers explored the effect of small hairpin RNA (shRNA) targeting LASS2/TMSG1 on the invasion and metastasis of human prostate carcinoma cell line PC-3M-2B4 with low metastatic potential and its functional interaction with V-ATPase and the results revealed that silencing of LASS2/TMSG1 enhances invasion and metastasis of PCA cell through increase of V-ATPase activity. These results establish LASS2/TMSG1 as a promising therapeutic target for advanced prostate cancer.

There has also been indication of the connection between LASS2/TMSG1 and tumor invasion metastasis in breast cancer cells. It was discovered that LASS2/TMSG1 inhibited cell growth in vitro by increasing apoptosis and changing cell cycle distribution. Furthermore, the V- ATPase activity and extracellular hydrogen ion concentration were significantly decreased and the activity of secreted matrix metalloproteinase-2 (MMP-2) was downregulated in cells overexpressing LASS2/TMSG1. It was proposed that LASS2/TMSG1 may inhibit growth and invasion of breast cancer cell in vitro through decreasing V- ATPase activity and extracellular hydrogen ion concentration and inactivating secreted MMP-2. The findings may provide a promising target for cancer metastasis diagnosis and therapy.

Researchers also found that LASS2 expression was significantly lower in drug-resistant Michigan Cancer Foundation-7/adriamycin (MCF-7/ADR) human breast cancer cells than the drug-sensitive MCF-7 cells, and low expression of LASS2 was associated with poor prognosis in patients with breast cancer. It was further revealed that the overexpression of LASS2 in MCF-7/ADR cells increased the chemosensitivity to multiple chemotherapeutic agents, including doxorubicin (Dox), whereas LASS2 knockdown in MCF-7 cells decreased the chemosensitivity. A corresponding increase in apoptosis in the LASS2-overexpressing cells following Dox exposure was detected, showing that the overexpression of LASS2 increased the susceptibility to Dox cytotoxicity. This suggested that LASS2 is involved in chemotherapeutic outcomes and low LASS2 expression may predict chemoresistance.

As mentioned above, expression of LASS2 has been reported in carcinomas of the prostate, liver, breast and human bladder cancer cell lines. Moreover, researchers confirmed that LASS2 was a direct target of miR-9 in bladder cancer cells. Transfection of miR-9 mimic downregulated LASS2 expression. LASS2 transfection downregulated Bcl-2 and expression, which were induced by miR-9 mimic in both cell lines. In conclusion, these results indicate that miR-9 upregulation might be associated with malignant phenotype of bladder cancer.

References:

Xu, X., et al. "Silencing of LASS2/TMSG1 enhances invasion and metastasis capacity of prostate cancer cell." Journal of Cellular Biochemistry 115.4(2014):731-743.
Mei, F., et al. "LASS2/TMSG1 inhibits growth and invasion of breast cancer cell in vitro through regulation of vacuolar ATPase activity. " Tumor Biology 36.4(2015):2831-2844.
Fan, S., et al. "LASS2 enhances chemosensitivity of breast cancer by counteracting acidic tumor microenvironment through inhibiting activity of V-ATPase proton pump. " Oncogene 32.13(2013):1682-1690.
Yu, Wenjuan, et al. "A novel tumor metastasis suppressor gene LASS2/TMSG1 interacts with vacuolar ATPase through its homeodomain." Journal of Cellular Biochemistry 114.3(2013):570-583.
Zhao, Qinghua, et al. "Expression of a tumor-associated gene, LASS2, in the human bladder carcinoma cell lines BIU-87, T24, EJ and EJ-M3." Experimental & Therapeutic Medicine 5.3(2013):942-946.

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