guanosine-monophosphate and Carcinoma--Squamous-Cell

VILIP-1 (visinin-like protein 1) is downregulated in various human squamous cell carcinoma (SCC). In a mouse skin SCC model VILIP-1 expression is reduced in aggressive tumor cells, accompanied by reduced cAMP levels. Overexpression of VILIP-1 in aggressive SCC cells led to enhanced cAMP production, in turn causing a reduction in invasive properties. Moreover, in primary neurons and neuronal tumor lines VILIP-1 enhanced cGMP signaling. Here, we set out to determine whether and how cAMP and cGMP signaling contribute to the VILIP-1 effect on enhanced SCC model cell migration, and thus most likely invasiveness in vivo. We found stronger increase in cGMP levels in aggressive, VILIP-1-negative SCC cells following stimulation of guanylyl cyclases NPR-A and -B with the natriuretic peptides ANP and CNP, respectively. Incubation with ANP or 8Br-cGMP to increase cGMP levels further enhanced the migration capacity of aggressive cells, whereas cell adhesion was unaffected. Increased cGMP was caused by elevated expression levels of NPR-A and -B. However, the expression level of VILIP-1 did not affect cGMP signaling and guanylyl cyclase expression in SCC. In contrast, VILIP-1 led to reduced migration of aggressive SCC cells depending on cAMP levels as shown by use of adenylyl cyclase (AC) inhibitor 2',3'-dideoxyadenosine. Involvement of cAMP-effectors PKA and EPAC play a role downstream of AC activation. VILIP-1-positive and -negative cells did not differ in mRNA expression of ACs, but an effect on enhanced protein expression and membrane localization of ACs was shown to underlie enhancement of cAMP production and, thus, reduction in cell migration by VILIP-1.

Topics: Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Animals; Atrial Natriuretic Factor; Blotting, Western; Carcinoma, Squamous Cell; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cyclic AMP; Cyclic GMP; Dideoxyadenosine; Guanosine Monophosphate; Humans; Mice; Microscopy, Fluorescence; Neurocalcin; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction; Skin Neoplasms

In order to examine the cyclic nucleotides (cGMP) role in carcinoma growth and invasivity. We analyzed two cell lines, LSHT29 and 17GT, and tissues in patients with carcinoma and malignant tissues with (N+) and without (N-) lymph node metastases. Higher cGMP levels in pathological samples suggest a strong correlation between intracellular cGMP concentration and carcinoma progression.

Topics: Carcinoma; Carcinoma, Squamous Cell; Cell Line, Tumor; Chromatography, High Pressure Liquid; Cyclic GMP; Disease Progression; Gingival Neoplasms; Guanosine Monophosphate; Humans; Indicators and Reagents; Lymphatic Metastasis; Mouth Neoplasms; Quinolines