Membrane Protein Metabolism in UNG-Activated NCAPH and RFC4 Subnetworks for Viral HCC|blood Cancer Development Via Inside-Out Microtubule Binding

Background: Our aim is to compute NCAPH and RFC4 subnetworks containing CDKN3 (feedback) for the novel molecular and cellular mechanisms of HCC (HBV or HCV) related cancer development from high UNG-activated upstream network. Methods: Non-SMC condensin I complex subunit H (NCAPH) and replication factor C subunit 4 (RFC4) common molecular and knowledge subnetworks containing cyclin-dependent kinase inhibitor 3-CDKN3 (feedback) related to cancer by references were identied in HCC (HBV or HCV), based on our established signicant high expression uracil DNA glycosylase (UNG)-activated upstream Gene (protein) reconstruction network inference (GRNInfer) and Database for Annotation, Visualization and Integrated Discovery (DAVID). Results: Our results show the common molecules MAPT interaction with CDKN3 with RRM2 with HIST1H3H from UNG-activated upstream GRNInfer database; The common biological process and molecular function of MAPT as microtubule binding; HIST1H3H as cellular protein metabolic process from UNG-activated upstream DAVID database; The common cellular component of UNG, NCAPH, CDKN3, RRM2, HIST1H3H at nucleus; NCAPH, HIST1H3H at membrane; The common tissue distributions of NCAPH and RFC4 in Leukemiapromyelocytic(hl60), leukemialymphoblastic(molt4), etc. Conclusions: We propose and mutual positively verify membrane protein metabolism in UNG-activated NCAPH and RFC4 subnetworks for viral HCC|blood cancer development via inside-out microtubule binding.


Background
Cyclin-dependent kinase inhibitor 3 (CDKN3) is not only the more active molecule in our established high uracil DNA glycosylase (UNG)-activated network, but also CDKN3 (feedback) as the common molecule of non-SMC condensin I complex subunit H (NCAPH) and replication factor C subunit 4 (RFC4) subnetworks in HCC (HBV or HCV). CDKN3, NCAPH and RFC4 or the related family molecules have been previously published associations with cancer in the references. Such as, CDKN3 promotes tumor progression through RAD51 in esophageal cancer [1]. CDKN3 regulates cisplatin resistance to colorectal cancer via TIPE1 [2]. Levels of human replication factor C4 correlate with tumor progression and predict the prognosis for colorectal cancer [3]. DNA replication and sister chromatid cohesion 1 (DSCC1) of the replication factor complex CTF18-RFC is critical for colon cancer cell growth [4]. NCAPH is upregulated in endometrial cancer and associated with poor clinicopathologic characteristics [5]. Overexpression of NCAPH is upregulated and predicts a poor prognosis in prostate cancer [6]. However, NCAPH and RFC4 subnetworks containing CDKN3 (feedback) has not been explored for the novel molecular and cellular mechanisms of HCC (HBV or HCV) related cancer development from high UNG-activated upstream network.
In the paper, NCAPH and RFC4 feedback/up/downstream molecular subnetworks from our established signi cant high expression UNG-activated upstream Gene (protein) reconstruction network inference (GRNInfer) [7] database will be constructed in HCC (HBV or HCV) successively by signi cance analysis of microarrays (SAM) (fold change ≥ 2), Pearson positive correlation coe cient (CC ≥ 0.25) database with UNG, other mutual positive Pearson correlation (CC ≥ 0.25), respectively. NCAPH and RFC4 common molecular subnetworks containing CDKN3 (feedback) will be computed from high UNG-activated upstream GRNInfer database. NCAPH and RFC4 common biological process, molecular function, cellular component subnetworks containing CDKN3 (feedback) will be computed from high UNG-activated upstream Database for Annotation, Visualization and Integrated Discovery (DAVID) GOTERM_BP_DIRECT, GOTERM_MF_DIRECT,GOTERM_CC_DIRECT [8,9]. NCAPH and RFC4 common and different tissue distributions will be calculated from high UNG-activated upstream DAVID GNF_U133A_QUARTILE and UNIGENE_EST_QUARTILE database.
Methods 225 signi cant high expression molecules in 25 HCC (HBV or HCV) were identi ed based on 6144 genes compared with the corresponding low expression of 25 no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) in GSE10140-10141 [10,11] (public free from NCBI) by SAM [12] (http://wwwstat.stanford.edu/~tibs/SAM/). Data were processed using a log base of two and two unpaired classes with minimum fold change (≥ 2). A false-discovery rate of 0% was chosen.
Low and high expression Pearson positive correlation coe cient (CC ≥ 0.25) molecules with UNG were calculated in no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) and HCC (HBV or HCV) from our established Pearson correlation coe cient database of total 225 signi cant expression molecules by SPSS. Low and high UNG-activated upstream molecular lists in no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) and HCC (HBV or HCV) were calculated from our established signi cant low and high expression UNG activation GRNInfer database. GRNInfer is a tool used to construct the activation and inhibition feedback/up/downstream molecular network based on linear programming and decomposition procedure de ned by the following equation: The other mutual positive Pearson correlation (CC ≥ 0.25) molecules except UNG were computed in notumor hepatitis/cirrhotic tissues (HBV or HCV infection) based on low UNG-activated upstream molecular list. Low UNG-activated upstream molecular network based on the corresponding mutual positive Pearson correlation database was constructed in no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) from our established signi cant low expression UNG activation GRNInfer database.
Low UNG-activated upstream knowledge network was identi ed in no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) from our established signi cant low expression UNG activation DAVID database (https://david.ncifcrf.gov/). Low UNG-activated upstream common biological process, molecular function, cellular component network was set up in no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) from low UNG activation DAVID GOTERM_BP_DIRECT, GOTERM_MF_DIRECT, GOTERM_CC_DIRECT database. Low UNG-activated upstream common tissue distribution network was set up in no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) from low UNG activation DAVID GNF_U133A_QUARTILE and UNIGENE_EST_QUARTILE database.
The other mutual positive Pearson correlation (CC ≥ 0.25) molecules except UNG were computed in HCC (HBV or HCV) based on high UNG-activated upstream molecular list. High UNG-activated upstream molecular network based on the corresponding mutual positive Pearson correlation database was set up in HCC (HBV or HCV) from our established signi cant high expression UNG activation GRNInfer database. NCAPH and RFC4 feedback/up/downstream direct and indirect molecular subnetwork containing CDKN3 (feedback) in HCC (HBV or HCV) was constructed from our established signi cant high expression UNGactivated upstream GRNInfer database, respectively. NCAPH and RFC4 common molecular subnetworks containing CDKN3 (feedback) in HCC (HBV or HCV) were computed from our established NCAPH and RFC4 feedback/up/downstream direct and indirect molecular database.
High UNG-activated upstream knowledge network in HCC (HBV or HCV) was identi ed from our established signi cant high expression UNG activation DAVID database. NCAPH and RFC4 common biological process, molecular function, cellular component subnetwork containing CDKN3 (feedback) was set up in HCC (HBV or HCV) from our established signi cant high expression UNG-activated upstream DAVID GOTERM_BP_DIRECT, GOTERM_MF_DIRECT, GOTERM_CC_DIRECT database, respectively. NCAPH and RFC4 common and different tissue distributions were set up in HCC (HBV or HCV) from high UNG-activated upstream DAVID GNF_U133A_QUARTILE and UNIGENE_EST_QUARTILE database.
NCAPH and RFC4 common biological process and molecular function subnetworks containing CDKN3 (feedback) were identi ed MAPT as microtubule binding; HIST1H3H as cellular protein metabolic process from high UNG-activated upstream DAVID GOTERM_BP_DIRECT and GOTERM_MF_DIRECT database.
NCAPH and RFC4 common cellular component subnetwork containing CDKN3 (feedback) was selected  Discussion NCAPH and RFC4 common molecular subnetworks and the related family members have been reported relationship with cancer including BUB1B (upstream), MAPT (upstream), CDKN3 (feedback), RRM2 (downstream), HIST1H3H (downstream) in the references. For instance, prevalence of germline mutations in BUB1B in individuals with early-onset colorectal cancer [13]. MAPT is a promising independent prognostic marker and tumor suppressive protein of clear cell renal cell carcinoma [14]. LncRNA TTN-AS1 regulates RRM2 to promote breast cancer progression [15]. KMT2A histone methyltransferase contributes to colorectal cancer development via promoting cathepsin Z transcriptional activation [16].
Our results show the common molecules MAPT interaction with CDKN3 with RRM2 with HIST1H3H; The common biological process and molecular function of MAPT as microtubule binding; HIST1H3H as cellular protein metabolic process in HCC (HBV or HCV) from our established high UNG-activated upstream GRNInfer, DAVID GOTERM_BP_DIRECT and GOTERM_MF_DIRECT database ( Fig. 1-2, Table 1, Supp 4-6). Therefore, we put forward and mutual positively verify protein metabolism in UNG-activated NCAPH and RFC4 subnetworks for viral HCC development via microtubule binding.
Low UNG-activated upstream molecular network in no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) was identi ed as NKX2_5 activation to UNG from our established signi cant low expression UNG activation GRNInfer database (Supp 1-2). Low UNG-activated upstream common biological process and molecular function network shows UNG, CIAO1, NKX2_5, REG3A as protein binding; UNG, NKX2_5 as negative regulation of apoptotic process from our established low UNG activation DAVID GOTERM_BP_DIRECT and GOTERM_MF_DIRECT database (Supp 3). We put forward negative regulation of apoptotic process in low UNG-activated upstream network for no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) development via protein binding. Low UNG-activated upstream common cellular component network demonstrates UNG, NKX2_5 at nucleus from our established low UNG activation DAVID GOTERM_CC_DIRECT database. Low UNGactivated upstream most common tissue distribution network was identi ed Tonsil from our established low UNG activation DAVID GNF_U133A and UNIGENE_EST database (Supp 3). We put forward negative regulation of apoptotic process in low UNG-activated upstream network for no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) and tonsil development via nucleus protein binding, and negatively verify our hypothesis.

Conclusion
We put forward and mutual positively verify membrane protein metabolism in UNG-activated NCAPH and RFC4 subnetworks for viral HCC|blood cancer development via inside-out microtubule binding, and also negatively verify our hypothesis in low UNG-activated upstream network of no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection). Other UNG-activated upstream molecular and knowledge subnetworks containing CDKN3 (feedback) will be computed and the hypotheses proposed for the whole systemic molecular and cellular mechanisms of HCC (HBV or HCV) related cancer development in the future.

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