Increased Expression of Myosin Light Chain Kinase mRNA Is Related to Metastasis in Non-Small Cell Lung Cancer

Abstract

Background: The invasiveness of tumor cells depends in large part on their motility, which in turn depends on cytoskeletal function. A major cytoskeletal component involved in cell motility is myosin II, the classical form of myosin first identified in muscle but also expressed in nonmuscle cells. Myosin II is activated by myosin light chain kinase (MLCK), which phosphorylates it on its regulatory light chain. In this context, the contribution made by MLCK to tumor cell motility and invasiveness has been investigated extensively in vitro, but clinical evidence of such a contribution has been lacking. In the present study, therefore, we examined the role of MLCK in the metastasis of non-small cell lung cancer (NSCLC) in a clinical setting. Methods: We measured MLCK mRNA expression in tumor samples from 39 NSCLC patients using real-time semiquantitative reverse transcription polymerase chain reaction carried out in a LightCycler. We then correlated MLCK mRNA expression with known clinicopathological factors. Results: We found that levels of MLCK mRNA expression were higher in patients who showed disease recurrence and distant metastasis than in those who did not. Moreover, the 3-year disease-free survival rate among patients showing lower levels of MLCK mRNA expression [log₁₀(MLCK/GAPDH) <1.4] was significantly greater than among those showing higher MLCK mRNA expression [log₁₀(MLCK/GAPDH) ≧1.4] (87.5 vs. 50.0%; log-rank test, p = 0.021). Conclusion: These findings are the first clinical evidence that expression of MLCK is correlated with disease recurrence and distant metastasis in NSCLC.

Proteomic analysis of stage I primary lung adenocarcinoma aimed at individualisation of postoperative therapy

“…However, there is still a profound lack of understanding of the exact mechanical roles of myosin IIA during cell migration. A recent clinical study of patients with NSCLC found a significant positive correlation between the expression levels of myosin light chain kinase (which activates myosin II) and the likelihood of disease recurrence and metastasis (Minamiya et al, 2005), indicating that myosin IIA activation could be a factor contributing to metastasis. A key role for myosin IIA in cancer cell metastasis has been further suggested, indirectly, by a number of published studies focusing on the small calcium-binding protein, metastasin-1.…”

The actin cytoskeleton in cancer cell motility

“…ROCK and MLCK have been shown to play distinct but complementary roles in the regulation of MLC phosphorylation, actin structures and motility of cells in 2D tissue culture conditions [107][108][109][110]. Elevated MLCK expression has been detected in numerous tumour types [111][112][113][114] and cancer cell lines [115][116][117] suggesting that increased MLCK activity resulting from overexpression or increased calcium transients might act to drive cancer cell motility in vivo, possibly in co-operation with ROCK. ZIPK has recently been shown to be phosphorylated and activated by ROCK [118], and can phosphorylate common substrates including MLC [45], MYPT1 [119] and CPI-17 [68].…”

Actin-bundling proteins in cancer progression at a glance

“…High levels of the myosin kinase Rho-associated protein kinase 1 (ROCK1) are associated with poor survival in breast cancer patients (Lane et al, 2008) and correlate with poor tumour differentiation, muscle invasion and lymph node metastasis in bladder cancer (Kamai et al, 2003). One clinical study showed a positive correlation between myosin light chain kinase, which activates myosin II, with disease recurrence and metastasis in non-small cell lung cancer (Minamiya et al, 2005). Better reagents for the detection of active myosin II or specific enrichment of myosin II isoforms are needed for further clinical studies (Vicente-Manzanares et al, 2009).…”

“…Aberrant association of filamin-A with the prion protein PrPA correlates with worse prognosis in pancreatic cancer. A secreted variant of filamin-A in the blood correlates with highgrade astrocytomas and metastatic breast cancer (Ai et al, 2011;Alper et al, 2009;Anilkumar et al, 2003;Bedolla et al, 2009;Burton et al, 2010;Castoria et al, 2011;Kwon et al, 2008;Li et al, 2010b;Li et al, 2010c;Li et al, 2009;Loy et al, 2003;Smith et al, 2007;Sy et al, 2010;Uramoto et al, 2010;Zhou et al, 2011) Formins (Minamiya et al, 2005;Oslejskova et al, 2008) T-plastin (T-fimbrin) Microvilli of epithelial and mesenchymal cells Crosslinks F-actin into straight bundles T-plastin expression is enhanced in cisplatin-resistant human cancer cell lines (Hisano et al, 1996) L-plastin Crosslinks actin into orthogonal networks by forming tetramers. Forms a scaffold for signalling complexes and keeps SMAD3 or SMAD4 inhibited.…”