Identification of genes associated with gall bladder cell carcinogenesis: Implications in targeted therapy of gall bladder cancer

Abstract

Gall bladder cancer (GBC) is becoming a very devastating form of hepatobiliary cancer in India. Every year new cases of GBC are quite high in India. Despite recent advanced multimodality treatment options, the survival of GBC patients is very low. If the disease is diagnosed at the advanced stage (with local nodal metastasis or distant metastasis) or surgical resection is inoperable, the prognosis of those patients is very poor. So, perspectives of targeted therapy are being taken. Targeted therapy includes hormone therapy, proteasome inhibitors, signal transduction and apoptosis inhibitors, angiogenesis inhibitors, and immunotherapeutic agents. One such signal transduction inhibitor is the specific short interfering RNA (siRNA) or short hairpin RNA (shRNA). For developing siRNA-mediated therapy shRNA, although several preclinical studies to evaluate the efficacy of these key molecules have been performed using gall bladder cells, many more clinical trials are required. To date, many such genes have been identified. This review will discuss the recently identified genes associated with GBC and those that have implications in its treatment by siRNA or shRNA.

Keywords: Advanced therapy of gall bladder cancer; Gall bladder cancer; Gene biomarker; Prognosis; Targeted therapy; siRNA mediated therapy.

Figure 1

Current scenario of gall bladder cancer treatment strategies. T1a, T1b, T2, T3, and T4 stand for the different T stages of gall bladder cancer. Usually, the T1a, T1b, and T2 tumors could be removed by surgery but this should be confirmed only after a CT scan. T3 and T4 tumors usually cannot be removed by surgery and other approaches are taken to treat them. GBC: Gall bladder cancer.

Figure 2

Mechanism of MAP kinase activation by some of the target genes. ERBB members: EGFR/ Her2/ErbB3/ErbB4; GRB: A serine protease and shortened form of Granzyme B; EZRIN: A protein needed for activation of RAS; SOS: Guanosine nucleotide exchange factor helps in the activation of RAS, the name derived from Son of Sevenless gene; RAS: A G protein, the name is derived from rat sarcoma virus; RAF: Serine threonine protein kinases and shortened form of rapidly accelerated fibrosarcoma; MAP kinase: Protein kinases and shortened form of mitogen-activated protein kinase; EGFR, HER2/neu, and CD44 are receptors embedded in the phospholipid bilayer and A-RAF protein is present in the cytoplasm; EGFR, HER2/neu, CD44, and ARAF activate the protein kinase, MAPK which ultimately results in the survival of tumor cells; HA: Hyaluronic acid; EGF: Epidermal growth factor; EGFR: Epidermal growth factor receptors.