Pyruvate kinase muscle isozymes (PKMs) have crucial roles in regulating metabolic changes during carcinogenesis. A switch from PKM1 to PKM2 isoform was thought to lead to aerobic glycolysis promoting carcinogenesis, and was considered as one of the cancer signatures. However, recent evidence has argued against the existence of PKM isoform switch and related metabolic effects during cancer progression. We compared the effects of PKM1 and PKM2 in cell invasiveness and metastasis of pancreatic ductal adenocarcinoma (PDAC). Both PKM1 and PKM2 expression affected cell migration and invasion abilities of PDAC cells, but only knockdown of PKM2 suppressed metastasis in a xenograft model. By comparing the established PKM2 mutants in the regulation of cell invasion, we found that PKM2 may control cell mobility through its protein kinase and phopho-peptide binding abilities. Further survey for PKM2-associated proteins identified PAK2 as a possible phosphorylation target in PDAC. In vitro binding and kinase assays revealed that PKM2 directly phosphorylated PAK2 at Ser20, Ser141, and Ser192/197. Knockdown of PKM2 decreased PAK2 protein half-life by increasing ubiquitin-dependent proteasomal degradation. Moreover, we identified PAK2 as an HSP90 client protein and the mutation at Ser192/197 of PAK2 reduced PAK2-HSP90 association. Knockdown of PAK2 diminished in vitro cell mobility and in vivo metastatic ability of PKM2 overexpressed PDAC cells. PKM2 and PAK2 protein expression also positively correlated with each other in PDAC tissues. Our findings indicate that PKM2-PAK2 regulation is critical for developing metastasis in PDAC, and suggest that targeting the PKM2/HSP90/PAK2 complex has a potential therapeutic value in this deadly disease.

The long noncoding (lnc)RNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), plays a crucial role in the development of hepatocellular carcinoma (HCC). However, potential genetic variants (single nucleotide polymorphisms, SNPs) in MALAT1 that affect the susceptibility and progression of HCC have rarely been explored. Three tagging SNPs, viz., rs3200401 C > T, rs619586 A > G, and rs1194338 C > A, in MALAT1 were genotyped by a TaqMan allelic discrimination assay in 394 HCC patients and 1199 healthy controls. A stratified analysis showed that younger patients (<55 years) with the MALAT1 rs619586 G allele had a decreased risk of HCC under a codominant model (AOR = 0.289, 95% CI: 0.108–0.773, p = 0.013) and dominant model (AOR = 0.286, 95% CI: 0.107–0.765, p = 0.013). Female patients and patients with a smoking habit who carried the CA + AA genotype of rs1194338 had a lower risk of developing vascular invasion (p = 0.049) and a high Child–Pugh grade (B or C) (p = 0.036), respectively. Under the dominant model, smokers with the MALAT1 rs3200401 CT + TT genotype had a higher frequency of hepatitis B virus (HBV) infection (p = 0.034). Moreover, the aspartate aminotransferase was higher in patients with the rs3200401 CT + TT genotype. Furthermore, analyses of clinical datasets revealed that MALAT1 expression level was gradually unregulated during HCC development from normal liver, cirrhotic liver, dysplastic liver to HCC and correlated with poor survival rates in HCC patients, especially in the hepatitis virus-infected population.

◥Although new generations of EGFR-tyrosine kinase inhibitors (EGFR-TKI) have been developed for the treatment of patients with non-small cell lung cancer (NSCLC) with EGFR-mutant tumors, TKI resistance often returns as a result of additional EGFR mutations. In addition to seeking for next-generation EGFR-TKI, developing novel EGFR-targeting strategies may hold the key to overcome the vicious cycle of TKI resistance. Endocan is known as a receptor tyrosine kinase ligand enhancer in tumorigenesis, but the impact of endocan on EGFR-driven NSCLC progression remains unknown. In this study, higher endocan levels were found in lung tumors compared with cancer-free tissues and correlated with poor prognosis in patients with NSCLC harboring mutant EGFR; circulating endocan levels were also significantly higher in patients with mutant EGFR. Endocan facilitated EGFR signaling via direct binding and enhancing of the EGF-EGFR interaction and supported the growth of tumors driven by mutated EGFR. Activated EGFR in turn upregulated expression of endocan via JAK/STAT3 and ERK/ELK cascades, thus forming a positive regulatory loop of endocan-EGFR signaling. On the basis of the binding region between endocan and EGFR, we designed therapeutic peptides and demonstrated promising therapeutic effects in xenografts harboring EGFR mutations including TKI-resistant T790M. Together, our findings highlight the novel interaction between endocan and EGFR and new opportunities to effectively target endocan-EGFR regulatory axis in patients with TKI-resistant NSCLC.Significance: Endocan is a novel and critical regulator of EGF/EGFR signaling and serves as an alternative target of EGFR-TKI resistance in NSCLC.

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