Five candidate FR genes, including integral membrane protein 2B (ITM2B), lysophosphatidic acid receptor 6 (LPAR6), motilin receptor (MLNR), calcium-binding protein 39-like (CAB39L), and ADP ribosylation factor-like GTPase 11 (ARL11), were identified as potential initiating drivers of bladder carcinogenesis.
Cell expansion is driven by distinct forerunner genes; for example, lysophosphatidic acid receptor 6 (LPAR6) triggers the expansion of intermediate uroprogenitor cells, leading to the development of papillary luminal cancer, whereas calcium-binding protein 39-like (CAB39L) drives the expansion of basal uroprogenitor cells, leading to the development of basal cancer.
In humans, it has been related to hair growth since a mutation of LPAR6 was found in patients with hypotrichosis simplex, an alopecia-causing disorder .
De Santis et al., "Lysophosphatidic acid receptor LPAR6 supports the tumorigenicity of hepatocellular carcinoma," Cancer Research, vol.
Based on the hypothesis of steroid dependency of the proliferation-stimulating LPAR, the researchers assessed the expressions of LPAR1 to LPAR6 in the presence of AA by propagating prostate cancer cell lines, namely PC-3 (highly metastatic) and LNCaP (low metastatic potential).
AA treatment was also verified to also target proliferative factors LPAR1, LPAR3, LPAR4, LPAR5 and LPAR6.
Mutations in the LPAR6
(MIM 609239) and LIPH (MIM 607365) genes have been reported to cause autosomal recessive WH/hypotrichosis phenotype in various families.6,7 The LPAR6
and LIPH genes have been shown to have a common signalling pathway and are involved in hair growth in humans.8 The LPAR6
gene encodes lysophosphatidic acid receptor 6 (LPAR6
), whereas, the LIPH codes for lipase H (or a membrane-associated phosphatidic acid-selective phospholipase A1a [mPA-PLA1a]) that produce 2-acyl lysophosphatidic acid (LPA).8,9 LPA plays an important role in various biological functions and is a ligand of LPAR6
.8,9 The protein products of LPAR6
and LIPH gene are abundantly expressed in the inner root sheath (IRS) of the hair follicle.
On the other hand, LPAR4, LPAR5, and LPAR6
are expressed widely but at relatively low levels.