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Mesothelioma (MESO) is a rare and aggressive cancer of the mesothelium (lining of internal organs), where the main risk factor is asbestos exposure. MESO is classified based on three histological cell types (epithelioid, sarcomatoid, and biphasic), and predominately impacts pleural and peritoneal tissues (1). The malignant pleural form is highly lethal, and the treatment is typically surgery accompanying chemotherapy and radiotherapy. Regardless of the treatment, when diagnosis of MESO is made, survival is short, and the prognosis is poor (1). New molecular understanding will benefit biomarker discovery for early diagnosis and could allow improved therapeutic approach by discovering new molecular targets.
Many genes present in the network have a known association with MESO as represented in the QKG, namely ADAM10, APC, ATIC, BAP1, BCL10, CDKN2A, CDKN2B, CTNNB1, DHFR, EP300, FOSL1, GART, HSP90AB1, INHBA, NF2, PDCD1, TUBA1C, TUBA4A, TUBB4A, TUBB4B, TYMS, and WNT3a. A few examples will be discussed below. ADAM10 overexpression in malignant pleural MESO promotes invasiveness through N-Cadherin (CDH2) fragmentation (2). BAP1, a deubiquitinase, is a tumor suppressor gene involved in key biological processes such as proliferation, differentiation, and apoptosis, cell cycle progression, genome stability, and DNA repair, and loss-of-function BAP1 mutations are commonly found in malignant MESO (3). Many known genes have deletion mutations in MESO (CDKN2, CDKN2B, CTNNB1, NF2) and combinations of BAP1 deletions with NF2, CDKN2A, and CDKN2B deletions have been shown to accelerate MESO progression and to present a highly aggressive phenotype in a mouse model (4). With respect to treatments, pemetrexed has been approved in combination with platinum drugs (like cisplatin) for malignant pleural mesothelioma in specific settings (5, QKG). Pemetrexed is a folate analog and a metabolic inhibitor of DHFR (Dihydrofolate reductase) or GART (glycinamide ribonucleotide formyltransferase). EP300 functions as a histone acetyltransferase and recent study indicated its inhibition as a potential anti-tumor mechanism to decrease MESO progression in a mouse model, showing that EP300 promotes the growth of MESO and is a potential therapeutic target (6). Finally, as for many cancers, immune checkpoint inhibitors such as Nivolumab targeting PDCD1 have been approved recently for treatment of unresectable advanced malignant pleural mesothelioma (QKG).
The network contains an additional twenty-two genes predicted to be associated with MESO: AMOT, AMOTL1, AMOTL2, CLSTN1, COMT, EIF3H, ELMO1, GRK6, GTF2F2, HMGCR, LEFTY2, MED12, MED13L, MLF1, NBN, NCOA3, OTUB2, PTBP1, Saa3, SNAI2, STK38L, and YAP1. None of these currently have known connections with MESO directly in our QKG. However, many have direct or indirect molecular connections with cancer progression or tumorigenesis.
A few examples in that context are discussed briefly. Notably, the Hippo pathway is known to regulate organ development and tumorigenesis by controlling the activation status of the oncogene YAP1. Targeting the YAP1/TAZ complex by small molecule (K-975) has shown anti-tumor efficacy in malignant pleural MESO xenografts model (7). Moreover, two inhibitors (verteporfin and CA3) of YAP1/TAZ activate apoptosis and suppress the cancer stem cell phenotype in immortal mesothelioma cell lines model, demonstrating the important role of YAP1 in MESO progression (8). CLSTN (calsyntenin-1), a transmembrane protein and a member of the cadherin superfamily, is generally involved in mediating axonal anterograde transport of certain types of vesicles. Its alternatively spliced forms have a role in EMT, a key step in tumor metastasis. Recent studies indicated that alternative splicing of CLSTN1 resulted in at least two isoforms that differ in length. Silencing of the short CLSTN1 isoform accelerated EMT and silencing of the long isoform promoted cell death (9). This suggests that the alternative splicing isoform of CLSTN1 may have an important role in MESO progression, although isoforms are not included in our disease networks. G protein-coupled receptor kinase 6, GRK6, deactivates GPCRs by phosphorylating the activated forms and GRK6 is known to be involved in the metastatic process of many cancers (HCC, LUAD, MM) to name a few. Recent studies indicated that overexpression of GRK6 is associated with lower survival in CRC suggesting this gene as an independent predictor for poor survival in the CRC patients (10). Mediator complex subunit 12, MED12, is an important regulator of transcription via activation of CDK8 kinase (QKG). Mutations in MED12 results in cell cycle dysregulation in many cancers, where depending on the type, either deletion or overexpression of MED12 may promote tumorigenesis. One of the effects of reduced expression of MED12 is the upregulation of the TGF-B signaling and the induction of EMT and possible resistance to chemotherapy in colon and lung cancer (11). Finally, Myeloid leukemia factor-1, MLF1, is an oncoprotein involved in hematopoiesis and in cell cycle regulation, and is upregulated in lung cancer cell lines and human lung cancer tissue samples. Knock-down experiments demonstrated that MLF1 promotes the proliferation of lung cancer cells while diminishing apoptosis, indicating it as a potential therapeutic target (12).
1. Štrbac D, et al. (2022) Int J Mol Sci. 23(4):1975. PMID: 35216091
2. Sépult C, et al. (2019) Oncogene. 38(18):3521-3534. PMID: 30651596
3. Malakoti F, et al. (2022) Cancer Cell Int. 22(1):176. PMID: 35501851
4. Badhai J, et al. (2020) J Exp Med. 2020. 217(6): e20191257. PMID: 32271879
5. Hedy L Kindler HL, et al. (2018) J Clin Oncol, 36(13):1343-1373. PMID: 29346042
6. Liu Y, et al. (2013) Nat Med 19(9):1173-7. PMID: 23955711
7. Kaneda A, et al. (2020). Am J Cancer Res, 10(12):4399-4415. PMID: 33415007
8. Kandasamy S, et al. (2020). Mol Cancer Res (3):343-351. PMID: 31732616
9. Hu X, et al. (2020). Nat Commun 11(1):486. PMID: 31980632
10. Tao R, et al. (2018) Oncol Lett 15(4):5879-5886. PMID: 29552218
11. Gonzalez CG, et al. (2022) Oncol Lett. ; (3):74. PMID: 35111243
12. Li X, et al. (2018) Int J Clin Exp Pathol. 11(7):3533-3541. PMID: 31949731
Many genes present in the network have a known association with MESO as represented in the QKG, namely ADAM10, APC, ATIC, BAP1, BCL10, CDKN2A, CDKN2B, CTNNB1, DHFR, EP300, FOSL1, GART, HSP90AB1, INHBA, NF2, PDCD1, TUBA1C, TUBA4A, TUBB4A, TUBB4B, TYMS, and WNT3a. A few examples will be discussed below. ADAM10 overexpression in malignant pleural MESO promotes invasiveness through N-Cadherin (CDH2) fragmentation (2). BAP1, a deubiquitinase, is a tumor suppressor gene involved in key biological processes such as proliferation, differentiation, and apoptosis, cell cycle progression, genome stability, and DNA repair, and loss-of-function BAP1 mutations are commonly found in malignant MESO (3). Many known genes have deletion mutations in MESO (CDKN2, CDKN2B, CTNNB1, NF2) and combinations of BAP1 deletions with NF2, CDKN2A, and CDKN2B deletions have been shown to accelerate MESO progression and to present a highly aggressive phenotype in a mouse model (4). With respect to treatments, pemetrexed has been approved in combination with platinum drugs (like cisplatin) for malignant pleural mesothelioma in specific settings (5, QKG). Pemetrexed is a folate analog and a metabolic inhibitor of DHFR (Dihydrofolate reductase) or GART (glycinamide ribonucleotide formyltransferase). EP300 functions as a histone acetyltransferase and recent study indicated its inhibition as a potential anti-tumor mechanism to decrease MESO progression in a mouse model, showing that EP300 promotes the growth of MESO and is a potential therapeutic target (6). Finally, as for many cancers, immune checkpoint inhibitors such as Nivolumab targeting PDCD1 have been approved recently for treatment of unresectable advanced malignant pleural mesothelioma (QKG).
The network contains an additional twenty-two genes predicted to be associated with MESO: AMOT, AMOTL1, AMOTL2, CLSTN1, COMT, EIF3H, ELMO1, GRK6, GTF2F2, HMGCR, LEFTY2, MED12, MED13L, MLF1, NBN, NCOA3, OTUB2, PTBP1, Saa3, SNAI2, STK38L, and YAP1. None of these currently have known connections with MESO directly in our QKG. However, many have direct or indirect molecular connections with cancer progression or tumorigenesis.
A few examples in that context are discussed briefly. Notably, the Hippo pathway is known to regulate organ development and tumorigenesis by controlling the activation status of the oncogene YAP1. Targeting the YAP1/TAZ complex by small molecule (K-975) has shown anti-tumor efficacy in malignant pleural MESO xenografts model (7). Moreover, two inhibitors (verteporfin and CA3) of YAP1/TAZ activate apoptosis and suppress the cancer stem cell phenotype in immortal mesothelioma cell lines model, demonstrating the important role of YAP1 in MESO progression (8). CLSTN (calsyntenin-1), a transmembrane protein and a member of the cadherin superfamily, is generally involved in mediating axonal anterograde transport of certain types of vesicles. Its alternatively spliced forms have a role in EMT, a key step in tumor metastasis. Recent studies indicated that alternative splicing of CLSTN1 resulted in at least two isoforms that differ in length. Silencing of the short CLSTN1 isoform accelerated EMT and silencing of the long isoform promoted cell death (9). This suggests that the alternative splicing isoform of CLSTN1 may have an important role in MESO progression, although isoforms are not included in our disease networks. G protein-coupled receptor kinase 6, GRK6, deactivates GPCRs by phosphorylating the activated forms and GRK6 is known to be involved in the metastatic process of many cancers (HCC, LUAD, MM) to name a few. Recent studies indicated that overexpression of GRK6 is associated with lower survival in CRC suggesting this gene as an independent predictor for poor survival in the CRC patients (10). Mediator complex subunit 12, MED12, is an important regulator of transcription via activation of CDK8 kinase (QKG). Mutations in MED12 results in cell cycle dysregulation in many cancers, where depending on the type, either deletion or overexpression of MED12 may promote tumorigenesis. One of the effects of reduced expression of MED12 is the upregulation of the TGF-B signaling and the induction of EMT and possible resistance to chemotherapy in colon and lung cancer (11). Finally, Myeloid leukemia factor-1, MLF1, is an oncoprotein involved in hematopoiesis and in cell cycle regulation, and is upregulated in lung cancer cell lines and human lung cancer tissue samples. Knock-down experiments demonstrated that MLF1 promotes the proliferation of lung cancer cells while diminishing apoptosis, indicating it as a potential therapeutic target (12).
1. Štrbac D, et al. (2022) Int J Mol Sci. 23(4):1975. PMID: 35216091
2. Sépult C, et al. (2019) Oncogene. 38(18):3521-3534. PMID: 30651596
3. Malakoti F, et al. (2022) Cancer Cell Int. 22(1):176. PMID: 35501851
4. Badhai J, et al. (2020) J Exp Med. 2020. 217(6): e20191257. PMID: 32271879
5. Hedy L Kindler HL, et al. (2018) J Clin Oncol, 36(13):1343-1373. PMID: 29346042
6. Liu Y, et al. (2013) Nat Med 19(9):1173-7. PMID: 23955711
7. Kaneda A, et al. (2020). Am J Cancer Res, 10(12):4399-4415. PMID: 33415007
8. Kandasamy S, et al. (2020). Mol Cancer Res (3):343-351. PMID: 31732616
9. Hu X, et al. (2020). Nat Commun 11(1):486. PMID: 31980632
10. Tao R, et al. (2018) Oncol Lett 15(4):5879-5886. PMID: 29552218
11. Gonzalez CG, et al. (2022) Oncol Lett. ; (3):74. PMID: 35111243
12. Li X, et al. (2018) Int J Clin Exp Pathol. 11(7):3533-3541. PMID: 31949731
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