DLC1 as a regulator of proliferation, invasion, cell cycle, and apoptosis in cutaneous squamous cell carcinoma

Abstract

Increasing evidence has demonstrated that the tumor suppressor gene deleted in liver cancer-1 (DLC1) is tightly implicated in the development and progression of tumors and is verified to be downregulated in a variety of tumors. However, the roles and precise molecular mechanisms of DLC1 in cutaneous squamous cell carcinoma (cutaneous SCC) remain to be elucidated. In the present study, we confirmed the reduced level in cutaneous SCC tissues and cells, and DLC1 mRNA relative level in cutaneous SCC tissues with lymph node metastasis (0.801 ± 0.079) was markedly lower than those without lymph node metastasis (1.245 ± 0.071) (P < 0.0001). Importantly, the survival rates of patients with low DLC1 level were lower than those with high DLC1 level (P = 0.0051). Further investigation revealed that DLC1 overexpression inhibited proliferation and arrested cell cycle at G0/G1 phase in A431 cells, which may be tightly associated with upregulation of p21 protein and downregulation of cyclin D1 and cdk2 proteins. Moreover, the decreases of FAK and p-FAK as well as the increase of E-cadherin level mediated by elevated DLC1 level suppressed invasion in A431 cells. Additionally, DLC1 overexpression induced apoptosis coupled with elevations of Bax level and caspase-3 activity and decrease of Bcl-2 level in A431 cells. Taken altogether, our data presented herein suggest that DLC1 plays a pivotal role in the development and progression of cutaneous SCC, which may be in part achieved by regulating the signaling pathway related to proliferation, invasion, cell cycle, and apoptosis in cutaneous SCC cells.

Active nuclear IKK correlates with metastatic risk in cutaneous squamous cell carcinoma

“…We found that SCCderived A431 cells, previously tested for their invasiveness and metastatic capacity in vivo [46,49], show high levels of activated IKK in the nucleus mainly corresponding to the previously identified p45-IKKa isoform (Fig. 3a), compared with the low amounts of activated full-length IKKa or b (85/87 kDa, respectively).…”

8p deletion is strongly linked to poor prognosis in breast cancer

“…68,69 It will thus be interesting to see if breast cancers with 8p-loss might respond better to neoadjuvant chemotherapy as compared to those lacking this alteration. The fact that 8p deletions were markedly associated with rapid cell proliferation is potentially caused by deletion-dependent down-regulation of several wellknown cell-cycle control genes located at 8p21, 8p22 and 8p23, including for example LZTS1, an inhibitor of the Cdk1/cyclin B1 complex, 23 PINX1, which prolongs G0/S1 phase, 70 DLC1, an inducer of apoptosis, 71 and MTUS1, which delays progression of mitosis by prolonging metaphase. 21 Further steps for identification of putative tumor suppressor genes would include comparison between expression and copy numbers of 8p genes followed by functional studies.…”

Tumor-suppressor genes, cell cycle regulatory checkpoints, and the skin

“…[ 4 ] Cyclin D1 seems to be downregulated in specific skin cancers, especially in squamous cell carcinoma (SCC) by an altered TSG such as the gene Deleted in Liver Cancer 1 (DLC1). [ 5 ]…”

“…TSGs can induce skin cancers as a result of a loss of their normal function, i.e., these proteins suppress the development of cancer. [ 1 2 3 4 5 ] A recent review documented 716 human TSG (637 coding and 79 noncoding genes), 628 mouse TSG, and 567 rat TSG. [ 1 2 3 4 5 6 7 ] Since a single normal allele will express the wild-type TSG, the majority of human TSGs are recessive; specifically, both alleles must be defective for the cell to be susceptible to tumor development.…”

“…[ 1 2 3 4 5 ] A recent review documented 716 human TSG (637 coding and 79 noncoding genes), 628 mouse TSG, and 567 rat TSG. [ 1 2 3 4 5 6 7 ] Since a single normal allele will express the wild-type TSG, the majority of human TSGs are recessive; specifically, both alleles must be defective for the cell to be susceptible to tumor development. TSGs act as cell cycle repressors and/or promoters of apoptosis through 1) interruption of the cell cycle, 2) prevention of cell division, 3) halting of the cell cycle if DNA damage is not yet repaired, 4) induction of apoptosis if DNA damage cannot be repaired, and 5) promotion of cell adhesion and contact inhibition.…”